leptin and Liver-Cirrhosis

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

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Chronic liver disease (CLD) is a major health problem worldwide. Non-alcoholic fatty liver disease (NAFLD), chronic hepatitis C (CHC), chronic hepatitis B (CHB), and alcoholic liver disease (ALD) are the most common etiologies of CLD. Liver biopsy is the gold standard for assessment of liver fibrosis, however, it is an invasive method. This review attempts to evaluate the usefulness of serum adiponectin, serum leptin, serum ferritin, serum transforming growth factor-β1 (TGF-β1), and serum platelet derived growth factor-BB (PDGF-BB) as non-invasive markers in the diagnosis of liver fibrosis/cirrhosis. A systematic search in MEDLINE, Web of Science, Scopus, and local databases was performed to identify articles published in English or Persian as of November 2017. Studies conducted among CLD patients, with biopsy proven fibrosis/cirrhosis, and providing sufficient details of patients' clinicopathological characteristics were included. In the 95 studies included, there were a total of 15,548 CLD patients. More than 83% of studies were carried out in Asia and Europe. The relationship between liver fibrosis/cirrhosis and serum levels of ferritin, adiponectin, leptin, TGF-β1, and PDGF-BB was assessed in 42, 33, 27, nine, and three studies, respectively. Serum levels of the markers, particularly ferritin, could successfully predict liver fibrosis/cirrhosis, however, these data might not be clinically replicated and further studies are needed.

Topics: Adiponectin; Becaplermin; Biomarkers; Chronic Disease; Ferritins; Humans; Leptin; Liver Cirrhosis; Transforming Growth Factor beta1

Liver fibrosis is a multifaceted process that occurs as a consequence of chronic liver injury. This process is characterized by inflammation, activation of matrix-producing cells, matrix deposition and remodeling, and epithelial cell regeneration. In subjects with chronic liver damage, fibrogenesis is favored by the presence of obesity and insulin resistance, which are also relevant risk factors for the development and progression of nonalcoholic steatohepatitis (NASH). It is now well-known that adipose tissue is not only involved in energy storage but also functions as an endocrine organ that secretes various bioactive substances known as adipokines. This term identifies a group of polypeptide molecules, which exert local, peripheral and/or central actions. Additionally to their well-established role in controlling adipose tissue physiology, energy homeostasis, inflammation and immune function, adipokines have been shown to be involved in different obesity-related diseases, such as hypertension, atherosclerosis and type 2 diabetes. In liver diseases, the biologic actions of these factors may contribute to the mechanisms leading to NASH. In this review, we focus on the role of adipokines in liver fibrogenesis and discuss their potential as regulators of this pathological condition and as targets for future pharmacological treatment strategies of chronic liver diseases.

Topics: Adipokines; Adiponectin; Humans; Leptin; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

Liver fibrosis can progress to cirrhosis, which is considered a serious disease. The Child-Pugh score and the model of end-stage liver disease score have been established to assess residual liver function in patients with liver cirrhosis. The development of portal hypertension contributes to ascites, variceal bleeding and further complications in these patients. A transjugular intrahepatic portosystemic shunt (TIPS) is used to lower portal pressure, which represents a major improvement in the treatment of patients. Adipokines are proteins released from adipose tissue and modulate hepatic fibrogenesis. These proteins affect various biological processes that are involved in liver function, including angiogenesis, vasodilation, inflammation and deposition of extracellular matrix proteins. The best studied adipokines are adiponectin and leptin. Adiponectin protects against hepatic inflammation and fibrogenesis, and leptin functions as a profibrogenic factor. These and other adipokines are supposed to modulate disease severity in patients with liver cirrhosis. Consequently, circulating levels of these proteins have been analyzed to identify associations with parameters of hepatic function, portal hypertension and its associated complications in patients with liver cirrhosis. This review article briefly addresses the role of adipokines in hepatitis and liver fibrosis. Here, studies having analyzed these proteins in systemic blood in cirrhotic patients are listed to identify adipokines that are comparably changed in the different cohorts of patients with liver cirrhosis. Some studies measured these proteins in systemic, hepatic and portal vein blood or after TIPS to specify the tissues contributing to circulating levels of these proteins and the effect of portal hypertension, respectively.

Topics: Adipokines; Adiponectin; Blood Proteins; Chemokines; Cytokines; Galectin 3; Galectins; GPI-Linked Proteins; Hepatitis; Humans; Hypertension, Portal; Intercellular Signaling Peptides and Proteins; Interleukin-6; Lectins; Leptin; Liver; Liver Cirrhosis; Nicotinamide Phosphoribosyltransferase; Portal Vein; Portasystemic Shunt, Transjugular Intrahepatic; Resistin

Aging is associated with dysregulation of glucose and lipid metabolism. Various factors that contribute to the dysregulation include both modifiable (e.g. obesity, insulin resistance) and non-modifiable risk factors (age-associated physiologic changes). Although there is no linear relationship between aging and prevalence of non-alcoholic fatty liver disease, current data strongly suggests that advanced age leads to more severe histological changes and poorer clinical outcomes. Hepatic lipid accumulation could lead to significant hepatic and systemic consequences including steatohepatitis, cirrhosis, impairment of systemic glucose metabolism and metabolic syndrome, thereby contributing to age-related diseases. Insulin, leptin and adiponectin are key regulators of the various physiologic processes that regulate hepatic lipid metabolism. Recent advances have expanded our understanding in this field, highlighting the role of novel mediators such as FGF 21, and mitochondria derived peptides. In this review, we will summarize the mediators of hepatic lipid metabolism and how they are altered in aging.

Topics: Adiponectin; Aging; Fibroblast Growth Factors; Gene Expression Regulation, Developmental; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Liver Cirrhosis; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; Signal Transduction

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease, which is often accompanied by obese and/or type II diabetes mellitus. Approximately one-third of NASH patients develop hepatic fibrosis. Hepatic stellate cells are the major effector cells during liver fibrogenesis. Advanced liver fibrosis usually proceeds to cirrhosis and even hepatocellular carcinoma, leading to liver failure, portal hypertension and even death. Currently, there are no approved agents for treatment and prevention of liver fibrosis in human beings. Curcumin, the principal curcuminoid of turmeric, has been reported to show antitumor, antioxidant, and anti-inflammatory properties both in in vitro and in vivo systems. Accumulating data shows that curcumin plays a critical role in combating liver fibrogenesis. This review will discuss the inhibitory roles of curcumin and update the underlying mechanisms by which curcumin targets in inhibiting hepatic stellate cell activation.

Topics: Animals; Curcumin; Diabetes Mellitus, Type 2; Disease Models, Animal; Hepatic Stellate Cells; Humans; In Vitro Techniques; Leptin; Lipid Metabolism; Liver Cirrhosis; Oxidative Stress; Signal Transduction

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition characterized by insulin resistance, type 2 diabetes and fat accumulation in the liver that may cause hepatic inflammation and progressive scarring leading to nonalcoholic steatohepatitis (NASH) and irreversible liver damage (cirrhosis). As a result, there has been increased recognition of the need to assess and closely monitor individuals for risk factors of components of NAFLD and NASH, as well as the severity of these conditions using biomarkers.. To review the biomarkers used to diagnose and define the severity of NAFLD and NASH.. A comprehensive PubMed and Google Scholar literature search was performed using the terms "non-alcoholic fatty liver disease", "non-alcoholic steatohepatitis", as well as the name of each biomarker known to be used. Articles indexed between 2004 and 2014 were used. Each author read the publications separately and the results were discussed.. Biomarkers offer a potential prognostic or diagnostic indicator for disease manifestation, progression or both. Serum biomarkers, including total cholesterol, triglycerides, insulin resistance and C-peptide, have been used for many years. Emerging biomarkers, such as apolipoprotein A1, apolipoprotein B, leptin, adiponectin, free fatty acids, ghrelin and tumour necrosis factor-alpha, have been proposed as tools that could provide valuable complementary information to that obtained from traditional biomarkers. Moreover, markers of cell death and mitochondrial dysfunction (cytokeratins) represent powerful predictors of risk. For biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in sex and ethnic origin are a necessity.. The present review attempts to provide a comprehensive analysis of the emerging risk biomarkers of NAFLD and NASH, and to use the clinical significance and analytical considerations of each biomarker pointing out sentinel features of disease progression.

Topics: Adiponectin; Biomarkers; Ghrelin; Humans; Keratin-18; Leptin; Liver Cirrhosis; Liver Function Tests; Metabolomics; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Proteomics; Ultrasonography

Obesity is rapidly becoming pandemic and is associated with increased carcinogenesis, especially hepatocellular carcinoma (HCC). Adipose tissue is considered as an endocrine organ because of its capacity to secrete a variety of adipokines, such as leptin, adiponectin and resistin. Recently, adipokines have been demonstrated to be associated with kinds of chronic liver diseases including fibrosis, cirrhosis and carcinogenesis. Direct evidence is accumulating rapidly supporting the inhibitory and/or activating role of adipokines in the process of carcinogenesis and progression of human HCC. This review aims to provide important insight into the potential mechanisms of adipokines in the development of HCC.

Topics: Adiponectin; Adipose Tissue; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Disease Progression; Humans; Leptin; Liver Cirrhosis; Liver Neoplasms; Obesity; Resistin

Leptin is an adipocyte-derived hormone that plays a crucial role in energy homeostasis and lipid metabolism. Most of the biological effects of leptin are exerted through activation of the Janus kinase-2/signal transducer and activator of transcription-3 pathway. Signal transducer and activator of transcription-3 activation ultimately leads to an increased transcription and expression of suppressors of cytokine signaling-3, which acts as a feedback inhibitor by attenuating leptin signaling. Apart from inhibiting leptin signaling, suppressor of cytokine signaling-3 inhibits insulin signaling. Leptin increases with increasing fatty mass as a compensatory mechanism to preserve insulin sensitivity, but persistent hyperleptinemia is implicated in liver fibrinogenesis and carcinogenesis.. Considering this dual role of leptin in the liver pathophysiology, we hypothesized that leptin resistance may vary according to the different types of liver cells and nonalcoholic fatty liver disease progression.. It is speculated that recombinant leptin, proposed to be used in common forms of obesity or nonalcoholic fatty liver disease, might have serious unfavorable therapeutical drawbacks, through promotion of insulin resistance, fibrosis, and hepatocellular carcinoma.

Topics: Animals; Carcinoma, Hepatocellular; Disease Progression; Fatty Liver; Humans; Insulin Resistance; Janus Kinase 2; Leptin; Liver Cirrhosis; Liver Neoplasms; Signal Transduction; STAT3 Transcription Factor

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, whose pathogenesis begins with the accumulation of liver fat and is followed by the development of necro-inflammation and fibrosis. Recent evidence indicates that adipocytokines, polypeptides secreted by the adispose tissue, might play an important role in the pathogeneic process and progression of NAFLD. In this review, we explore the role of leptin, and in part of other adipocytokines, in the interference with hepatic injury associated with fatty infiltration, in the modulation of steatosis and fibrosis, in both experimental models of the disease and in the clinical practice. We also discuss the potential use of leptin as non-invasive marker for differentiating simple fatty liver from NAFLD, and the possible novel therapeutic strategies aimed at interfering with the leptin axis to dampen chronic liver inflammation and NAFLD.

Topics: Adipokines; Animals; Biomarkers; Drug Delivery Systems; Fatty Liver; Humans; Inflammation; Leptin; Liver Cirrhosis; Metabolic Syndrome

To highlight the metabolic or inflammatory components, deregulated in or pathogenic for the metabolic syndrome, that may, directly or indirectly, modulate hepatic fibrogenesis.. Advanced glycation end products signal profibrogenetic transformation of hepatic stellate cells. Altered adipocytokines favor insulin resistance and steatosis. They participate to the proinflammatory status of the metabolic syndrome. Among them, leptin has been shown to directly enhance fibrogenesis, whereas adiponectin has shown antifibrotic properties. The renin-angiotensin system, a component of arterial hypertension, is activated in the diseased liver, and there is convincing evidence that blockade of angiotensin II signaling attenuates fibrosis. Endocannabinoids, whose hepatic production and signaling capability are increased with insulin resistance and obesity, signal profibrotic response via the preponderant receptor, cannabinoid receptor 1, whereas antifibrotic and anti-inflammatory signals are rather generated via stimulation of cannabinoid receptor 2. Finally, recent data demonstrate that modulation of innate immunity, particularly modulation of natural killer and natural killer T cells, has potential roles in the resolution of steatohepatitis and fibrosis.. Several features associated with the metabolic syndrome can undoubtedly modulate liver fibrosis. More studies are needed to identify those that are prominent determinants of fibrosis in the metabolic syndrome and the benefit of their targeting for fibrosis prevention and treatment.

Topics: Adiponectin; Glycation End Products, Advanced; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Liver Cirrhosis; Metabolic Syndrome

Adipokines are polypeptides secreted in the adipose tissue in a regulated manner. While some of these molecules are expressed only by adipocytes, resident and infiltrating macrophages and components of the vascular stroma markedly contribute to expression of other adipokines. As a result, adipose tissue inflammation is associated with a modification in the pattern of adipokine secretion. Leptin, adiponectin, and resistin are the best-studied molecules in this class, but cytokines such as tumor necrosis factor or interleukin-6 are also secreted at high levels by the adipose tissue. Several other molecules have been recently identified and are actively investigated. Adipokines interfere with hepatic injury associated with fatty infiltration, differentially modulating steatosis, inflammation, and fibrosis. Several studies have investigated plasma levels of adiponectin in patients with nonalcoholic fatty liver disease, to establish correlations with the underlying state of insulin resistance and with the type and severity of hepatic damage. Hepatitis C is another disease where adipokines may represent a link between viral infection, steatosis, and metabolic disturbances. Identification of the mediators secreted by expanded adipose tissue and their pathogenic role is pivotal in consideration of the alarming increase in the prevalence of obesity and of the detrimental role that this condition exerts on the course of liver diseases.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Apelin; Fatty Liver; Hepatic Stellate Cells; Hepatitis, Viral, Human; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Liver; Liver Cirrhosis; Liver Diseases; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Retinol-Binding Proteins, Plasma; Tumor Necrosis Factor-alpha

Topics: Animals; Disease Models, Animal; Fatty Liver; Humans; Leptin; Liver; Liver Cirrhosis; Mice; Models, Animal; Rats; Receptors, Cell Surface; Receptors, Leptin

Leptin and adiponectin, the main metabolic products of adipose tissue, have been implicated in a wide spectrum of human diseases. Given the frequent presence of hepatic steatosis in several chronic liver diseases, there is currently increasing interest in the role of these adipokines in the development of hepatic steatosis and also in necroinflammation and fibrosis, mostly in patients with nonalcoholic fatty liver disease or chronic hepatitis C. According to experimental data, reduced adiponectin levels and increased leptin levels associated with leptin resistance, which are usually observed in obese patients with or without metabolic syndrome, may result in fat accumulation in the liver and in the enhancement of liver inflammation and mostly fibrogenesis. Increased leptin and decreased adiponectin serum levels have been detected initially in patients with nonalcoholic steatohepatitis and more recently in patients with chronic hepatitis C compared to healthy controls in most but not all studies, while the data on the associations between these adipokine levels and the severity of hepatic steatosis or fibrosis are still rather conflicting. However, several potential confounding parameters were not evaluated in all studies. Therefore, the associations between adipokines and liver histological lesions and their effects on liver cells should be evaluated further in prospective, carefully designed studies, including larger cohorts of patients with detailed assessment of metabolic and other potential confounding factors.

Topics: Adiponectin; Chronic Disease; Fats; Fatty Liver; Hepatitis C, Chronic; Humans; Leptin; Liver; Liver Cirrhosis; Liver Diseases

Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.

Topics: Angiotensin II; Animals; Humans; Hypertension, Portal; Leptin; Liver Cirrhosis; Liver Failure; Transforming Growth Factor beta

There is increasing evidence that visceral adipose tissue is a causative risk factor for fatty liver and nonalcoholic steatohepatitis. Adipose tissue-derived secretory proteins are collectively named adipocytokines. Obesity and mainly visceral fat accumulation impair adipocyte function and adipocytokine secretion and the altered release of these proteins contributes to hypertension, impaired fibrinolysis and insulin resistance. This review summarizes recent findings on the role of the adipocytokines adiponectin, leptin and resistin in the context of hepatic insulin resistance, fatty liver and liver fibrosis. Elevated levels of resistin antagonize hepatic insulin action and raise plasma glucose levels. Leptin exerts insulin-sensitizing effects, but obesity has been linked to leptin resistance and low levels of circulating leptin receptor, indicating that high levels of leptin cannot mediate its beneficial effects. Adiponectin improves insulin sensitivity; however, low circulating adiponectin is found in the obese state. Adiponectin is an anti-inflammatory protein, whereas leptin augments inflammation and fibrogenesis. Disturbed adipocytokine secretion might, therefore, promote hepatic steatosis and the development of nonalcoholic steatohepatitis. The beneficial effects of the therapeutic approaches so far tested in the treatment of fatty liver disease and fibrosis might be due to the modulation of these adipocytokines.

Topics: Adipocytes; Adipose Tissue; Cytokines; Fatty Liver; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Liver Cirrhosis; Obesity; Viscera

Leptin is being recognized as a multifunctional cytokine with diverse actions on body weight, energy expenditure, glucose homeostasis, reproduction, hemopoiesis and wound repair. This commentary describes some evidences related with its possible role in liver diseases, particularly, in fat deposition, inflammation and fibrosis.

Topics: Humans; Leptin; Liver Cirrhosis; Liver Diseases

This chapter reviews recent evidence that the sympathetic nervous system (SNS) regulates liver repair by modulating the phenotypes of hepatic stellate cells (HSCs), the liver's principal fibrogenic cells, and hepatic epithelial progenitors, i.e., oval cells. SNS nerve fibers touch HSCs and these cells express adrenoceptors, suggesting that HSCs may be targets for SNS neurotransmitters. HSCs also contain catecholamine biosynthetic enzymes, release norepinephrine (NE), and are growth-inhibited by adrenoceptor antagonists. In addition, HSCs from mice with reduced levels of NE grow poorly in culture and exhibit inhibited activation during liver injury. Finally, growth and injury-related fibrogenic responses are rescued by adrenoceptor agonists. Thus, certain SNS inhibitors (SNSIs) protect experimental animals from cirrhosis. Conversely, SNSIs enhance the hepatic accumulation of oval cells (OCs) in injured livers. This response is associated with improved liver injury. Because SNSIs do not affect the expression of cytokines, growth factors, or growth factor receptors that are known to regulate OCs, and OCs express adrenoceptors, it is conceivable that catecholamines influence OCs by direct interaction with OC adrenoceptors. Given evidence that the SNS regulates the viability and activation of HSCs and OCs differentially, SNSIs may be novel therapies to improve the repair of damaged livers.

Topics: Acetylcholine; Animals; Epithelial Cells; Humans; Leptin; Liver; Liver Cirrhosis; Mice; Neuropeptide Y; Neurotransmitter Uptake Inhibitors; Norepinephrine; Sympathetic Nervous System

Liver fibrosis is the consequence of chronic or repeated liver injury caused by hepatotoxic agents like alcohol and viruses, as well as immune and congenital metabolic disorders. Nonalcoholic fatty liver disease (NAFLD), caused by obesity and abnormal lipid metabolism, may be the latest known cause of liver fibrosis and cirrhosis. Furthermore, NAFLD with obesity can provide a terrain in which alcoholic and viral liver diseases, such as chronic hepatitis C, are prone to cause liver cirrhosis. Insulin, insulin-like growth factor (IGF)-1, peroxisome proliferator-activated receptors (PPARs), leptin, adiponectin, and preadipocyte factor-1/delta-like1 (Pref-1/dlk1) are hormones, growth factors, nuclear receptors, and cytokines that are actively involved in lipid metabolism. They share common target cells important in liver fibrosis, i.e., hepatic stellate cells (HSCs). Activation of HSCs is known to initiate and perpetuate liver fibrosis. Insulin and IGF-1 stimulate HSC activation and collagen production in vitro. However, IGF-1 alleviates liver fibrosis in vivo. Ligands of PPARy inhibit HSC activation and collagen synthesis in vivo and in vitro, and are helpful in decreasing liver fibrosis. But ligands of PPARbeta enhance proliferation of HSCs. Leptin is profibrogenic, and liver fibrosis is decreased in leptin- or leptin receptor-deficient mice. Adiponectin is, on the contrary, anti-fibrogenic. Extensive liver fibrosis may develop in adiponectin-knockout mice and is alleviated by administration of recombinant adiponectin. Pref-1/dlkl is implicated in fibrogenesis of the liver through its modulation of HSCs. The use of such biologically active molecules in lipid metabolism as ligands of PPARgamma and adiponectin might not help slim down a patient on the whole, but can potentially be used to halt the progression of liver fibrosis. Weight reduction, a strategy for controlling obesity and metabolic syndromes, may also be a tool for decreasing NAFLD and alleviating liver cirrhosis.

Topics: Adiponectin; Calcium-Binding Proteins; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Liver Cirrhosis; Membrane Proteins; Obesity; Peroxisome Proliferator-Activated Receptors; Peroxisomes; Repressor Proteins; Somatomedins

Liver cirrhosis in the advanced state is characterized by protein wasting, as indicated by the loss of muscle mass, hypoalbuminemia, and an abnormal amino acid profile. The protein wasting condition cirrhosis is associated with a poor prognosis and reduced survival. Poor nutrition, metabolic and hormonal abnormalities, and other disease-associated alterations may all concur to protein wasting. An understanding of the causes and mechanisms leading to protein wasting in cirrhosis may help in the development of nutritional interventions and new therapies.. Albumin and muscle protein turnover in cirrhotic patients have been studied in vivo with the aid of isotope dilution techniques or organ catheterization. Albumin synthesis appears to parallel liver function, i.e. the more compromised is the liver, the less is the albumin production rate. Meal-induced albumin synthesis is impaired even in compensated cirrhotic patients. Skeletal muscle protein synthesis is diminished in cirrhosis, and total muscle protein breakdown also appears to be increased, thus explaining the reduced muscle mass. Either hormone or substrate resistance, or newly involved substances (cytokines, insulin-like growth factor 1, leptin) may play a role in the reduced synthesis of both albumin and muscle proteins in liver cirrhosis.. Abnormalities of both albumin and muscle protein turnover have been demonstrated in liver cirrhotic patients. The possible role of the multiple hormonal and metabolic abnormalities of this disease, as well that of cytokines and other recently discovered substances, need to be investigated further.

Topics: Albumins; Cytokines; Humans; Insulin-Like Growth Factor I; Leptin; Liver Cirrhosis; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Myofibrils

Topics: Animals; Humans; Leptin; Liver Cirrhosis; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Non-alcoholic fatty liver disease (NAFLD) is the emerging cause of chronic liver disease globally and lack of approved therapies. Here, we investigated the feasibility of combinatorial effects of low molecular weight fucoidan and high stability fucoxanthin (LMF-HSFx) as a therapeutic approach against NAFLD. We evaluated the inhibitory effects of LMF-HSFx or placebo in 42 NAFLD patients for 24 weeks and related mechanism in high fat diet (HFD) mice model and HepaRG

Topics: Adiponectin; Adult; Aged; Animals; Cell Line; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Humans; Inflammation; Insulin Resistance; Leptin; Lipid Metabolism; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Middle Aged; Non-alcoholic Fatty Liver Disease; Polysaccharides; Xanthophylls; Young Adult

To evaluate the effect of Zhenggan Tang decoction on serum levels of leptin, adiponectin and insulin resistance on liver cirrhosis induced by chronic hepatitis B.. Sixty-six patients were recruited and randomly assigned either to a control group or to an intervention group, with 35 cases in the treatment and 31 in the control group respectively. Patients in the control group received inosine tablets and vitamin C treatment while patients in the treatment group were given Zhenggan Tang decoction additionally. After 3 months of treatment, the serum levels of leptin and adiponectin were detected and the index of insulin resistance calculated.. There were no significant difference between the serum levels of leptin, adiponectin and the index of insulin resistance seen in the control group before and after the treatment. Serum levels of leptin and adiponectin and the index of insulin resistance in treatment group were reduced significantly after the treatment (P < 0.05). There were significant difference in the serum levels of leptin and adiponectin between treat group and control group (P < 0.05).. Zhenggan Tang decoction seemed to have reduced the serum levels of leptin, adiponectin and the index of insulin resistance among cirrhotic patients that induced by chronic hepatitis B.

Topics: Adiponectin; Drugs, Chinese Herbal; Hepatitis B, Chronic; Humans; Insulin Resistance; Leptin; Liver Cirrhosis; Treatment Outcome

Pathologic changes in the liver are common in morbidly obese patients, and insulin resistance may potentiate the progression of nonalcoholic steatohepatitis to fibrosis and cirrhosis. This study investigates the impact of leptin and adiponectin in morbidly obese diabetic and nondiabetic patients with regard to histopathologic changes in the liver.. Thirty-seven morbidly obese patients who underwent bariatric surgery with liver biopsies were enrolled in the study. Fourteen were diabetic and 23 were nondiabetic. Intraoperative liver tissue was sent for histopathologic analysis and extraneous intraoperative tissue was snap-frozen in liquid nitrogen. Total RNA was extracted and RNA was reverse transcribed to cDNA. Real-time quantitative PCR was performed to determine relative gene expression levels. The data were analyzed using a logarithmic transformation and normalized by 18S ribosome expression. Student's t test was used for statistical analysis with p < or = 0.05 as significant.. Adiponectin expression was downregulated 4.4-fold (p < or = 0.05) in liver samples with evidence of inflammation on pathology. When hepatic inflammation was evaluated separately, there were no statistically significant differences in adiponectin levels between the diabetic and nondiabetic patients. However, overall adiponectin levels in hepatic samples of diabetic patients were 3.8-fold higher than those of nondiabetic patients (p < or = 0.05). There were no significant differences in leptin levels regardless of hepatic pathology or diabetic status.. This study illustrates that there is a downregulation of adiponectin in morbidly obese patients with inflammatory infiltrates in the liver. Variations in adiponectin levels could be an indicator of disease progression since inflammatory infiltrates are commonly associated with nonalcoholic steatohepatitis (NASH) in morbidly obese patients. Currently, we are using human myofibroblasts derived from livers of morbidly obese people to further investigate the molecular mechanisms involved in the progression of fatty liver to fibrosis and cirrhosis.

Topics: Adiponectin; Adult; Biopsy; Diabetes Complications; Disease Progression; Down-Regulation; Fatty Liver; Female; Gene Expression; Humans; Insulin Resistance; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged; Obesity, Morbid

Leptin has a particular profibrogenic role in the liver. We investigated whether IFN-alpha influences leptin production in patients with chronic hepatitis B (CHB) and C (CHC). Leptin was determined in serial samples from 63 CHB and 42 CHC IFN-alpha treated patients. Furthermore, we evaluated whether leptin alterations were associated with patients' characteristics.. Sera were investigated at serial time-points using an enzyme-linked-immunosorbent-assay. Controls consisted of 36 patients with autoimmune liver diseases and 44 healthy patients.. Leptin levels before IFN-alpha administration were higher in CHB and CHC compared to healthy (P<0.004) and diseased controls (P=0.0001). In CHB patients, we observed a significant reduction of leptin during IFN-alpha treatment and lasting for up to 6 months after the end of treatment, followed by an increase reaching pretreatment levels at 1.5 years after stopping therapy. The pattern of leptin alterations was similar in CHC patients where leptin's decrease was more pronounced at 6 months after the end of treatment. Biochemical or virological response to treatment was not associated with leptin reduction in both groups.. This study provides information on leptin kinetics during IFN-alpha treatment and follow-up in CHB and CHC patients and suggests IFN-alpha as a potential inhibitor of leptin production.

Topics: Adult; Aged; Antiviral Agents; Female; Follow-Up Studies; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Autoimmune; Humans; Interferon-alpha; Leptin; Liver Cirrhosis; Male; Middle Aged; Prospective Studies; Sex Characteristics; Treatment Outcome

Liver fibrosis is a potentially harmful chronic liver disease caused by various etiologies. There is currently no specific drug for liver fibrosis. Xiaochaihu Tang (XCHT) is a traditional formula combined of seven herbs, which was first recorded in the Treatise on Febrile Diseases in Han Dynasty of ancient China. It is widely used in clinic to hepatic protection, analgesic, antipyretic and anti-inflammatory treatment. And it has been recommended for treating chronic hepatitis and chronic cholecystitis in the latest guidelines for the diagnosis and treatment of liver fibrosis with integrated traditional and western medicine. However, the underlying regulatory mechanisms remain elusive.. This study aims to explore the therapeutic effects of XCHT on liver fibrosis and its underlying molecular mechanisms from the perspective of network pharmacology and experimental research.. Carbon tetrachloride (CCl. When treated with XCHT, liver fibrosis was alleviated in both mice models, showing as the improvement of liver function, the protection of hepatocytes, the inhibition of HSC activation and the reduction of hepatic collagen accumulation. 540 monomer components, 300 therapeutic targets, 109 signaling pathways, 246 GO biological processes, 77 GO cellular components, 107 GO molecular functions items and core targets were identified by network analysis. Then, 6-gingerol and baicalein were identified as the core components of anti-fibrosis effects of XCHT via leptin or Nrf2 signaling pathway. Furthermore, the experiment in vitro also validated the results.. Our study suggests XCHT could alleviate liver fibrosis through multi-targets and multi-pathways; 6-gingerol and baicalein are its core components which may play an important role via leptin or Nrf2 signaling pathway.

Topics: Animals; Drugs, Chinese Herbal; Leptin; Liver Cirrhosis; Mice; Molecular Docking Simulation; Network Pharmacology; NF-E2-Related Factor 2

Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for chronic kidney disease (CKD). Previous studies argued that leptin levels increase significantly with the progression of CKD. But the association between leptin and CKD has not been investigated in patients with NAFLD. Therefore, we conducted this study to establish whether increased leptin level is associated with CKD in NAFLD patients.. In our prospective study with a follow up period of six months thirty-five teetotaller biopsy-proven NAFLD patients were divided as groups with mild, versus advanced, fibrosis. Liver fibrosis was also assessed with Fibroscan. Serum leptin levels were measured by radioimmunoassay. For insulin resistance we used the homeostasis model assessment method (HOMA-IR). For the kidney function, we used the abbreviated formula Modification of Diet in Renal Disease (MDRD) formula, which estimates GFR. For statistical analysis, Student's-t test, Mann-Whitney test, linear regression-binary logistic regression analyses and the ROC curve analysis were used.. Advanced fibrosis and increased HOMA-IR were risk factors for decreased eGFR. Leptin correlated inversely with advanced fibrosis (p: 0.03) and low leptin was a risk factor for CKD (p: 0.02). In ROC curve analysis, advanced fibrosis and low leptin were risk factors for decreased eGFR (p: 0.007 and 0.004, respectively). Low leptin level was dependently associated with decreased eGFR.. Advanced fibrosis in NAFLD patients is a risk factor for CKD. Leptin correlated inversely with advanced fibrosis. Unlike the previous studies, which were not performed in NAFLD patients, we found decreased leptin in NAFLD patients with decreased eGFR. Low leptin level was found to be a dependent predictor for differentiating NAFLD patients with high risk for CKD.

Topics: Humans; Kidney; Leptin; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Prospective Studies; Renal Insufficiency, Chronic

Obese patients usually have hyperleptinemia and are prone to develop liver fibrosis. Leptin is intimately linked to liver fibrogenesis, a multi-receptor-driven disease. Gα-Interacting Vesicle-associated protein (GIV) functions as a multimodular signal transducer and a guanine nucleotide exchange factor for Gi controling key signalings downstream of diverse receptors. This study aimed to examine the roles of GIV in leptin-caused liver fibrosis and employed the culture-activated hepatic stellate cells (HSCs) and leptin-deficient mice, respectively. Results indicated that leptin upregulated GIV expression in HSCs. GIV was involved in leptin-induced HSC activation and liver fibrosis. GIV mediated leptin regulation of TIMP1, MMP9, PDGFβ receptor and TGFβ receptor and was required for leptin stimulating the pathways of Erk1/2, Akt1, and Smad3. GIV was also a mediator for leptin-regulation of Cyclin D1 and Caspase-3 activity but GIV reduced Caspase-3 level independently of leptin in vivo. Erk1/2 signaling, Egr1 and c-Jun were associated with the effect of leptin on GIV expression in HSCs. Leptin-induced Erk1/2 signaling increased Egr1 and p-c-Jun levels and promoted their binding to GIV promoter at the sites between -190 bp and -180 bp and between -382 bp and - 376 bp, respectively. Egr1 knockdown lessened leptin-upregulation of GIV in vitro and in vivo. In human cirrhotic livers, the increase in GIV protein level parallelled with the elevated p-Erk1/2 and Egr1 levels in HSCs. In summary, the unusual signal transducer GIV was identified as an important mediator in leptin-induced liver fibrosis. GIV may have significant implications in liver fibrosis progression of obese patients with hyperleptinaemia.

Topics: Animals; Carrier Proteins; Caspase 3; Humans; Leptin; Liver Cirrhosis; Mice; Microfilament Proteins; Obesity; Vesicular Transport Proteins

The purpose of this study was to evaluate the effect of curcumin, an active polyphenol, on the leptin induced lowering of miR-122 in Hepatic stellate cells (HSCs) in vivo and an animal model. Gene expression was evaluated by transfection assay, real-time PCR, or Western blot analysis. The liver fibrosis model of leptin deficient mouse was used for in vivo experiment. As a result, curcumin showed inhibitory effect on leptin induced lowering of the miR-122 in HSCs. Curcumin suppressed leptin induced sonic hedgehog (Shh) expression and blocked leptin induced Shh signaling pathway, which was essential for curcumin inhibition of the negative role of leptin in miR-122 expression in HSCs. The influence of curcumin on the negative effect of leptin on miR-122 level was followed by the attenuation of liver fibrosis caused by leptin in leptin-deficient mouse model. In conclusion, curcumin could reduce the decrease of miR-122 level in HSCs induced by leptin and inhibit liver fibrosis induced by leptin. These data may have potential implications to treat with liver fibrosis by elevating the expression of leptin in humans especially obese patients.

Topics: Animals; Curcumin; Disease Models, Animal; Hedgehog Proteins; Hepatic Stellate Cells; Humans; Leptin; Liver Cirrhosis; Mice; MicroRNAs

Leptin is an adipokine with roles in food intake and energy metabolism through its actions on neurons in the hypothalamus. The role of leptin in obesity and cardiovascular disorders is well documented. However, its influence on liver conditions such as cholestasis is poorly understood. The effects of exogenous leptin and leptin-neutralizing antibody on biliary hyperplasia, hepatic fibrosis, and inflammation in the multidrug resistance protein 2 knockout (Mdr2KO) mouse model of cholestasis were assessed by quantifying markers specific for cholangiocytes, activated hepatic stellate cells (HSCs), and cytokines. Serum and hepatic leptin were increased in Mdr2KO mice compared with FVB/NJ (FVBN) controls, and exogenous leptin enhanced biliary hyperplasia and liver fibrosis in Mdr2KO and FVBN mice. Leptin administration increased hepatic expression of C-C motif chemokine ligand 2 and IL-6 in Mdr2KO mice. In contrast, leptin-neutralizing antibody reduced intrahepatic bile duct mass and decreased HSC activation in Mdr2KO mice compared with FVBN controls. Sex-related differences were noted, with female Mdr2KO mice having more leptin than males. In cholangiocytes and LX2 cells in vitro, leptin increased phosphorylated Akt and stimulated cell proliferation. Leptin receptor siRNA and inhibitors of Akt phosphorylation impaired leptin-induced cell proliferation and proinflammatory cytokines. The current data suggest that leptin is abnormally increased in cholestatic mice, and excess leptin increases ductular reaction, hepatic fibrosis, and inflammation via leptin receptor-mediated phosphorylation of Akt in cholangiocytes and HSCs.

Topics: Animals; Antibodies, Neutralizing; Cholestasis; Cytokines; Disease Models, Animal; Female; Hepatic Stellate Cells; Hyperplasia; Inflammation; Leptin; Liver; Liver Cirrhosis; Male; Mice; Mice, Knockout; Proto-Oncogene Proteins c-akt; Receptors, Leptin

The renin-angiotensin-aldosterone system (RAAS) activation is the milestone in ascites formation. Hypertonic saline solution (HSS) has attracted considerable interest over the last years in ascites control. Other therapeutic models and concepts have been introduced to overcome diuretic resistance and control ascites. We aimed to evaluate the effects of adding HSS infusion and/or etilefrine to oral diuretics therapy on inflammatory and metabolic pathways, renal and systemic hemodynamics, and clinical outcomes by estimating the changes in selected biochemical and biological markers in cirrhotic patients with ascites.. Ninety cirrhotic patients with ascites were studied after administration of HSS infusion (n=25) or etilefrine tablets (n=25), or both (n=25) plus standard diuretics therapy (SDT), or SDT alone (n=15). Serum levels of interleukin-6 (IL-6), aldosterone, leptin, and C-reactive protein (CRP). Hepatic and renal functions were measured at baseline, after eight days, then after 38 days.. A significant reduction in serum IL-6, serum aldosterone, Child-Pugh score, MELD-Na score, and increase in serum leptin, and mean arterial pressure (p<0.05) were noted after 38 days in HSS and combination groups. A significant improvement in diuresis, in all groups, urinary sodium excretion, and creatinine clearance (p<0.05) were increased after 38 days in all groups except the SDT group.. The results suggest that HSS, etilefrine, and their combination plus SDT are superior to SDT alone for ascites control and can exert some benefits on clinical, systemic, inflammatory, renal, and metabolic pathways without renal or hepatic dysfunction.

Topics: Aldosterone; Ascites; Biomarkers; C-Reactive Protein; Creatinine; Diuretics; Etilefrine; Furosemide; Humans; Interleukin-6; Leptin; Liver Cirrhosis; Saline Solution, Hypertonic; Sodium

Beinaglutide has been approved for glucose lowering in type 2 diabetes mellitus (T2DM) in China. In addition to glycemic control, significant weight loss is observed from real world data. This study is designed to investigate the pharmacological and pharmacokinetic profiles of beinaglutide in different models.. The pharmacological efficacy of beinaglutide was evaluated in C57BL/6 and ob/ob mice after single administration. Pharmacokinetic profiles in mice were investigated after single or multiple administration. Sub-chronic pharmacological efficacy was investigated in ob/ob mice for two weeks treatment and diet-induced ob/ob mice model of nonalcoholic steatohepatitis (NASH) for four weeks treatment.. Beinaglutide could dose-dependently reduce the glucose levels and improve insulin secretion in glucose tolerance tests, inhibit food intake and gastric emptying after single administration. At higher doses, beinaglutide could inhibit food intake over 4 h, which results in weight loss in ob/ob mice after about two weeks treatment. No tachyphylaxis is observed for beinaglutide in food intake with repeated administration. In NASH model, beinaglutide could reduce liver weight and hepatic steatosis and improve insulin sensitivity. Signiant changes of gene levels were observed in fatty acid β-oxidation (Ppara, Acadl, Acox1), mitochondrial function (Mfn1, Mfn2), antioxidation (Sod2), Sirt1, and et al. SIGNIFICANCE: Our results characterize the pharmacological and pharmacokinetic profiles of beinaglutide in mice and supported that chronic use of beinaglutde could lead to weight loss and reduce hepatic steatosis, which suggest beinaglutide may be effective therapy for the treatment of obesity and NASH.

Topics: Animals; Antioxidants; Diabetes Complications; Diabetes Mellitus; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Liraglutide; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Oxidation-Reduction; Peptide Fragments; PPAR alpha; Weight Loss

Obese patients are often accompanied by hyperleptinemia and prone to develop liver fibrosis. Accumulating data including those obtained from human studies suggested the promotion role of leptin in liver fibrosis. The remodeling of the DNA methylation is an epigenetic mechanism for regulating gene expression and is essential for hepatic stellate cell (HSC) activation, a key step in liver fibrogenesis. Leptin increases the expression of methionine adenosyltransferase 2A (MAT2A) which is associated with DNA methylation and HSC activation. Curcumin, an active polyphenol of the golden spice turmeric, inhibits leptin-induced HSC activation and liver fibrogenesis. Thus, the present research aimed to investigate the influence of curcumin on the roles of leptin in MAT2A expression in HSCs.. The in vivo experiments were conducted by using leptin-deficient obese mice. The gene expressions were examined by Western blot, real-time PCR, promoter activity assay, and immunostaining analysis.. Curcumin reduced leptin-induced MAT2A expression. JNK signaling contributed to leptin-induced increase in MAT2A level, which could be interrupted by curcumin treatment. Curcumin inhibited leptin-induced MAT2A promoter activity by influencing MAT2A promoter fragments between -2,847 bp and - 2,752 bp and between -2,752 bp and +49 bp. The effect of curcumin on leptin-induced MAT2A expression paralleled the reductions in leptin-induced activated HSCs and liver fibrosis.. These results might have implications for curcumin inhibition of the liver fibrogenesis in obese patients with hyperleptinemia.

Topics: Animals; Curcumin; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Male; MAP Kinase Signaling System; Methionine Adenosyltransferase; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity

Most obese patients develop hyperleptinaemia. Leptin, mainly produced by adipocytes, demonstrates a promotional role in liver fibrosis. Hepatic stellate cell (HSC) activation, a key step in liver fibrogenesis, requires global reprogramming of gene expression. The remodeling of DNA methylation is a mechanism of the epigenetic regulation of gene expression. The biosynthesis of S-adenosylmethionine, a principle biological methyl donor, is catalyzed by methionine adenosyltransferase (MAT) such as MATⅡ which has been shown to promote HSC activation in vitro. This study was mainly aimed to determine the effect of leptin on MAT2A expression (the catalytic subunit of MATⅡ) in HSCs. Results showed that MAT2A knockdown reduced leptin-induced HSC activation and liver fibrosis in the leptin-deficient mouse model. Leptin promoted MAT2A expression in HSCs and increased MAT2A promoter activity. The axis of the β-catenin pathway/E2F-4 mediated the effect of leptin on MAT2A expression. Leptin-induced β-catenin signaling reduced E2F-4 expression and thus abated E2F-4 binding to MAT2A promoter at a site around -2779 bp, leading to an increase in the MAT2A promoter activity. These data might shed more light on the mechanisms responsible for liver fibrogenesis in obese patients with hyperleptinaemia.

Topics: Animals; beta Catenin; E2F4 Transcription Factor; Gene Expression Regulation; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Methionine Adenosyltransferase; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity

Obese patients, often accompanied by hyperleptinemia, are prone to develop liver fibrosis. A large body of data including the results from human studies suggested the promotion role of leptin, an adipocyte-derived hormone, in liver fibrosis. Hepatic stellate cell (HSC) activation, a crucial step in liver fibrogenesis, requires global reprogramming of gene expression which is regulated by multiple mechanisms including epigenetic regulation such as methylation of DNA. S-Adenosylmethionine is a principal biological methyl donor and its biosynthesis is catalyzed by a methionine adenosyltransferase (MAT) such as MATII. MATII consists of the catalytic subunit MAT2A and regulatory subunit MAT2B which are essential for HSC activation. The present research investigated the effect of leptin on the expression of Mat2b in HSCs in vitro and in a leptin-deficient mouse model. Results demonstrated that leptin significantly increased Mat2b expression. Leptin-induced Mat2b expression required the PI3K/AKT signaling pathway. c-Jun, a component of activator protein (AP1), was phosphorylated by leptin-induced PI3K/AKT signaling and thus potentiated its binding to the element around -964 bp in the Mat2b promoter. MAT2B was involved in leptin-induced HSC activation and liver fibrosis in a leptin-deficient mouse model. These results might broaden understanding of the mechanisms underlying the liver fibrogenesis in obese patients with hyperleptinemia. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Topics: Animals; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Male; Methionine Adenosyltransferase; Mice; Mice, Obese; Obesity; Phosphatidylinositol 3-Kinases; Phosphorylation; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-jun; Signal Transduction

Topics: Animals; Cell Line; Disease Models, Animal; Female; Gene Expression Regulation; Hepatocytes; Leptin; Liver Cirrhosis; Male; Mice, Knockout; Nitric Oxide Synthase Type II; Phenotype; Proteolysis; Tenascin

Liver fibrosis is a challenging global health problem resulting from chronic liver injury with no treatment currently available. It has been shown that activators for different peroxisome proliferator-activated receptor (PPAR) isoforms (α, γ, and δ) can affect different pathways in liver fibrosis. To evaluate the effects of the dual PPAR-α/γ agonist saroglitazar (SGZ) against thioacetamide (TAA)-induced fibrosis in rats, SGZ was administered for 6 weeks together with TAA injection. Administration of SGZ ameliorated TAA-induced elevation in hepatic biomarkers. SGZ was able to inhibit periportal and intralobular fibrous connective tissue proliferation, to decrease hydroxyproline content, and to lower alpha smooth muscle actin (α-SMA) protein expression. To unearth the antifibrotic mechanism of SGZ, the role of several fibrotic markers was studied. SGZ possesses inhibitory effect on protein levels of leptin, transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor-BB (PDGF-BB). Furthermore, SGZ rectified matrix degradation through decreasing tissue inhibitor of metalloproteinases-1 (TIMP-1). This study suggests that SGZ could have a possible antifibrotic effect via suppression of leptin that can repress TGF-β1 and PDFG-BB, with subsequent inhibition of TIMP-1.

Topics: Actins; Animals; Becaplermin; Leptin; Liver; Liver Cirrhosis; Male; Phenylpropionates; PPAR alpha; PPAR gamma; Pyrroles; Rats, Sprague-Dawley; Thioacetamide; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1

Nonalcoholic steatohepatitis (NASH) is prevalent in both economically developed and developing countries. Twenty percent of NASH progresses to cirrhosis with/without hepatocellular carcinoma, and there is an urgent need to find biomarkers for early diagnosis and monitoring progression of the disease. Using immunohistochemical and immunoelectron microscopic examination we previously reported that expression of matrix metalloproteinase-1 (MMP-1) increased in monocytes, Kupffer cells and hepatic stellate cells in early stage NASH. The present study investigated whether serum MMP-1 levels reflect disease activity and pharmaceutical effects in NASH patients.. We measured the serum levels of MMPs, tissue inhibitors of metalloproteinases (TIMPs), and several cytokines/chemokines in patients with histologically proven early and advanced stages of NASH and compared them with those in healthy controls.. Serum MMP-1 levels in stage 1 fibrosis, but not in the more advanced fibrosis stages, were significantly higher than in healthy controls (. These results suggest that serum MMP-1 levels represent disease activity and may serve as a potential biomarker for monitoring the progression of NASH.

Topics: Adult; Aged; Case-Control Studies; Chemokine CCL2; Female; Ghrelin; Granulocyte Colony-Stimulating Factor; Humans; Kupffer Cells; Leptin; Liver Cirrhosis; Male; Matrix Metalloproteinase 1; Middle Aged; Monocytes; Non-alcoholic Fatty Liver Disease; Severity of Illness Index

Insulin and leptin resistance are highly involved in metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Presently, no approved treatment is available. Actein is isolated from the rthizomes of Cimicifuga foetida, a triterpene glycoside, exhibiting important biological properties, such as anti-inflammatory, anti-cancer, and anti-oxidant activity. However, its effects on metabolic syndrome are poorly understood. The aims of the study were mainly to investigate the molecular mechanisms regulating insulin and leptin resistance, and lipogenic action of actein in high fat diet-fed mice. Our data indicated that actein-treated mice displayed lower body weight, epididymal and subcutaneous fat mass, as well as serum lipid levels. Also, improved insulin and leptin resistance were observed in actein-treated groups. Liver inflammation and fibrosis triggered by high fat diet were decreased for actein administration. Moreover, hepatic lipid accumulation was also reduced by actein along with reductions of hepatic de novo lipogenesis-linked signals in actein-treated rodents with high fat diet. High fat diet-induced activation of insulin receptor substrate 1/Forkhead box protein O1 (IRS1/FOXO1), Janus kinase 2 gene/signal transducer and activator of transcription (JAK2/STAT3) and Protein Kinase B/Glycogen synthase kinase 3 beta (AKT/GSK3β) pathways in liver was inhibited by actein, a potential mechanism by which hyperinsulinemia, hyperleptindemia and dyslipidemia were attenuated. Thus, the findings above might be of nutritional and therapeutic importance for the treatment of NAFLD.

Topics: Animals; Cell Line; Diet, High-Fat; Dyslipidemias; Fatty Liver; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Saponins; Triterpenes

Adipocytokine leptin promotes hepatic stellate cell (HSC) activation (a key step in liver fibrogenesis) and liver fibrosis. microRNA-122 (miR-122) is the most abundant liver-specific miRNA and was demonstrated to inhibit liver fibrosis and reduced HSC proliferation. Our previous study revealed that leptin reduced miR-122 level in HSCs. This study was aimed to investigate whether leptin affected miR-122 promoter and the underlying mechanisms in HSCs. Results showed that leptin inhibited miR-122 promoter activity. Forkhead box protein O1(FoxO1) bound to miR-122 promoter at a site around - 56 and thus promoted miR-122 promoter activity, which could be suppressed by leptin-induced phosphorylation of FoxO1 at serine 256. The PI3K/Akt signaling pathway was involved in leptin-induced phosphorylation of FoxO1 and the effect of leptin on miR-122 expression. Furthermore, FoxO1 increased miR-122 and pri-miR-122 (primary miR-122) levels in HSCs in vivo, and reduced leptin-induced HSC activation and liver fibrosis in ob/ob mouse (leptin deficient) model. In conclusion, leptin suppressed microRNA-122 expression by PI3K/Akt/foxO1 axis in HSCs. These results have potential implications for clarifying the mechanisms for liver fibrogenesis in obese patients with hyperleptinaemia.

Topics: Animals; Cells, Cultured; Forkhead Box Protein O1; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Mice, Obese; MicroRNAs; Phosphorylation; Promoter Regions, Genetic; Random Allocation

Topics: Adolescent; Blood Coagulation Disorders; Craniopharyngioma; Humans; Hypopituitarism; Leptin; Liver Cirrhosis; Male; Non-alcoholic Fatty Liver Disease; Obesity; Pituitary Neoplasms

Obese patients, often accompanied by hyperleptinemia, are prone to liver fibrogenesis. Leptin is an adipocyte-derived hormone and plays a promotion role in liver fibrosis. Sterol regulatory element binding protein-1c (SREBP1c) exerts a crucial role in inhibiting hepatic stellate cell (HSC) activation, a key step in liver fibrogenesis. Our previous studies indicated that leptin inhibited SREBP1c expression, contributing to leptin-induced HSC activation and liver fibrosis. microRNAs (miR) have emerged as important layers of regulatory control and regulate gene expression, and are implicated in numerous diseases. The present study revealed leptin up-regulation of miR-27a/b-3p levels in HSCs in vitro and in vivo. Three signaling pathways were required for leptin regulation of miR-27a/b-3p levels. miR-27a/b-3p could reduce SREBP1c and liver x receptor α (LXRα) levels, increased α-smooth muscle actin (α-SMA, a marker for HSC activation) and α1(I)collagen levels in cultured HSCs. miR-27a/b-3p regulation of SREBP1c and LXRα were independent of 3'-untranslated region of SREBP1c and LXRα mRNA. In vivo experiments further demonstrated the miR-27a/b-3p involved in leptin-associated decrease in SREBP1 level in HSCs, HSC activation, and liver fibrosis. These data might have potential implications for our understanding of molecular mechanisms underlying leptin roles in liver fibrogenesis of obese patients with hyperleptinaemia.

Topics: 3' Untranslated Regions; Actins; Animals; Collagen Type I; Disease Models, Animal; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Liver X Receptors; Mice; Mice, Inbred C57BL; Mice, Obese; MicroRNAs; RNA, Messenger; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Up-Regulation

Leptin is associated with metabolic disorders, which predispose one to non-alcoholic fatty liver disease (NAFLD). The role of leptin in NAFLD pathogenesis is not fully understood. We aim to investigate the association between serum leptin level and severity of NAFLD using U.S. nationally representative data.. Data were obtained from the United States Third National Health and Nutrition Examination Survey. NAFLD was defined by ultrasound detection and severity of hepatic steatosis in the absence of other liver diseases. The severity of hepatic fibrosis was determined by NAFLD fibrosis score (NFS). We used multivariate survey-weighted generalized logistic regression to evaluate the association between leptin level and the degree of NAFLD. We also performed subgroup analyses by body mass index (lean vs. classic NAFLD).. Among 4,571 people, 1,610 (35%) had NAFLD. By ultrasound findings, there were 621 people with mild, 664 with moderate, and 325 with severe steatosis. There were 885 people with low NFS (<-1.455, no significant fibrosis), 596 with intermediate NFS, and 129 with high NFS (>0.676, advanced fibrosis). Leptin levels for normal, mild, moderate and severe steatosis were 10.7±0.3 ng/mL, 12.1±0.7 ng/mL, 15.6±0.8 ng/mL, 16±1.0 ng/mL, respectively (trend P-value<0.001). Leptin levels for low, intermediate, and high NFS were 11.8±0.5 ng/mL, 15.6±0.8 ng/mL, 28.5±3.5ng/mL, respectively (trend P-value<0.001). This association remained significant even after adjusting for known demographic and metabolic risk factors. In the subgroup analysis, this association was only prominent in classic NAFLD, but not in lean NAFLD.. Serum leptin level is associated with the severity of NAFLD, especially in classic NAFLD patients.

Topics: Adult; Aged; Body Mass Index; Cross-Sectional Studies; Female; Humans; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Nutrition Surveys; Severity of Illness Index; Ultrasonography; Young Adult

The relationship between hepatitis B virus (HBV) infection, leptin and insulin resistance remains unclear. We hypothesised links between serum leptin and insulin resistance in non-diabetic patients with chronic viral hepatitis B infection and their relation to liver fibrosis.. We recruited 190 untreated patients with chronic HBV infection and 72 healthy controls. Serum leptin, fasting glucose, insulin, liver function tests (LFTs), C-peptide and Homeostasis model assessment-IR (HOMA-IR) were measured/calculated by ELISA and standard techniques.. Serum leptin, C-peptide (both P < 0.001), HOMA-IR (P = 0.021) and several LFTs were increased in patients with chronic HBV-infection. In multivariate regression analysis, both HOMA-IR (P = 0.003) and leptin (P = 0.002) were significant independent predictors of HBV infection. There were significant positive correlations (P < 0.01) between leptin and HOMA-IR (r = 0.81), between serum leptin and METAVIR activity (r = 0.95), and between HOMA-IR and BMI (r = 0.75), fasting glucose (r = 0.005), and fasting insulin (r = 0.81). Several LFTs, glucose and insulin correlated modestly (r = 0.61-0.69, P < 0.05) with leptin.. Serum leptin may be related to the rate of fibrosis progression in nondiabetic patients with chronic HBV infection. Follow-up by serial measurement of serum leptin and HOMA-IR in non diabetic HBV-infected patients may be used as a non-invasive marker of early liver fibrosis.

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Fasting; Female; Hepatitis B virus; Hepatitis B, Chronic; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged

There is a growing body of studies that show the important role of NS3 protein from hepatitis C virus in fibrosis. However, mechanisms of the effects of this protein on immune modulation of stellate cells remain to be investigated. Herein, the effect of NS3 protein on the expression level of suppressor of cytokine signaling (SOCS)1/3 and interleukin-24 (IL-24)-related genes was investigated in hepatic stellate cell (HSC), LX-2. Recombinant NS3 protein was added to LX-2 HSC culture. Leptin and standard medium treatments were also included in experiments as positive and negative controls, respectively. Total RNA was extracted from each well at 6, 12, and 24 h after NS3 addition. The expression levels of the fibrotic (transforming growth factor beta 1 [TGF-β], alpha-smooth muscle actin [α-SMA], and COL1A1), inflammatory (IL-6 and IL-24), IL-20R, IL-22R, and immunosuppressive genes (SOCS1 and SOCS3) were evaluated by real-time polymerase chain reaction (PCR). Recombinant NS3 protein induced activated phenotypes of LX-2 with a significant increase in the expression level of α-SMA COL1A1 (p < 0.0001) and TGF-β. Moreover, this exposure led to a meaningful elevation in the expression of IL-6. Furthermore, compared with leptin (control), after the stellate cell treatment with NS3, SOCS1 and SOCS3 gene expression induced at a comparable level. Compared with the control sample, the NS3 protein significantly increased the expression level of IL-24 and its related receptors, IL-20R and IL-22R. This study not only confirmed the previously proved inflammatory and fibrotic effect of this protein but also indicated that high expression levels of SOCS1, SOCS3, and IL-24 have a significant effect on HSC activation. Therefore, these two molecules can be used as a potential therapeutic target candidate.

Topics: Cells, Cultured; Gene Expression; Hepatic Stellate Cells; Humans; Immunologic Factors; Interleukin-6; Interleukins; Leptin; Liver Cirrhosis; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Viral Nonstructural Proteins

Nonalcoholic fatty liver disease (NAFLD) is independently linked to cardiometabolic morbidity and mortality. Low-grade inflammation, oxidative stress and ectopic fat, common features of chronic obstructive pulmonary disease (COPD), might contribute to the development of NAFLD.We aimed to investigate the prevalence of NAFLD and to evaluate the relationship between various types of liver damage and COPD severity, comorbidities and circulating inflammatory cytokines. Validated noninvasive tests (FibroMax: SteatoTest, NashTest and FibroTest) were used to assess steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis. Patients underwent an objective assessment of COPD comorbidities, including sleep studies. Biological parameters included a complete lipid profile and inflammatory markers.In COPD patients the prevalence of steatosis, NASH and fibrosis were 41.4%, 36.9% and 61.3%, respectively. In multivariate analysis, SteatoTest and FibroTest were significantly associated with sex, body mass index (BMI), untreated sleep apnoea and insulin resistance, and, in addition, COPD Global Initiative for Chronic Obstructive Lung Disease stage for SteatoTest. Patients with steatosis had higher tumour necrosis factor-α levels and those with NASH or a combination of liver damage types had raised leptin levels after adjustment for age, sex and BMI.We concluded that NAFLD is highly prevalent in COPD and might contribute to cardiometabolic comorbidities.

Topics: Adiponectin; Aged; Body Mass Index; C-Reactive Protein; Cohort Studies; Comorbidity; Female; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Liver Cirrhosis; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Resistin; Tumor Necrosis Factor-alpha

Obese patients, often accompanied by hyperleptinemia, are more likely to develop liver fibrosis. Leptin, an adipocyte-derived hormone, augments inflammatory in liver and promotes hepatic stellate cell (HSC) activation (a key step for liver fibrogenesis) and liver fibrosis. microRNA-122 (miR-122) is the most abundant liver-specific miRNA and can attenuate liver fibrosis. This study examined the effect of leptin on miR-122 level in HSCs in vivo and in vitro. Results demonstrated that leptin reduced the levels of both miR-122 (mature miR-122) and primary miR-122 (pri-miR-122). The effects of leptin on the levels of miR-122 and pri-miR-122 were through at least hedgehog pathway. Leptin-induced decrease in sterol regulatory element-binding protein-1c (SREBP-1c) has been shown to contribute to leptin-induced HSC activation. We revealed a mutual promotional effect between SREBP-1c and miR-122. Further experiments indicated that miR-122 inhibited leptin-induced liver fibrosis in leptin-deficient mouse model. These data have potential implications for clarifying the mechanisms of hepatic fibrogenesis associated with elevated leptin level in human such as obese patients.

Topics: Animals; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Mice; MicroRNAs; Sterol Regulatory Element Binding Protein 1

Liver fibrosis develops when hepatic stellate cells (HSC) are activated into collagen-producing myofibroblasts. In non-alcoholic steatohepatitis (NASH), the adipokine leptin is upregulated, and promotes liver fibrosis by directly activating HSC via the hedgehog pathway. We reported that hedgehog-regulated osteopontin (OPN) plays a key role in promoting liver fibrosis. Herein, we evaluated if OPN mediates leptin-profibrogenic effects in NASH.. Leptin-deficient (ob/ob) and wild-type (WT) mice were fed control or methionine-choline deficient (MCD) diet. Liver tissues were assessed by Sirius-red, OPN and αSMA IHC, and qRT-PCR for fibrogenic genes. In vitro, HSC with stable OPN (or control) knockdown were treated with recombinant (r)leptin and OPN-neutralizing or sham-aptamers. HSC response to OPN loss was assessed by wound healing assay. OPN-aptamers were also added to precision-cut liver slices (PCLS), and administered to MCD-fed WT (leptin-intact) mice to determine if OPN neutralization abrogated fibrogenesis.. MCD-fed WT mice developed NASH-fibrosis, upregulated OPN, and accumulated αSMA+ cells. Conversely, MCD-fed ob/ob mice developed less fibrosis and accumulated fewer αSMA+ and OPN+ cells. In vitro, leptin-treated HSC upregulated OPN, αSMA, collagen 1α1 and TGFβ mRNA by nearly 3-fold, but this effect was blunted by OPN loss. Inhibition of PI3K and transduction of dominant negative-Akt abrogated leptin-mediated OPN induction, while constitutive active-Akt upregulated OPN. Finally, OPN neutralization reduced leptin-mediated fibrogenesis in both PCLS and MCD-fed mice.. OPN overexpression in NASH enhances leptin-mediated fibrogenesis via PI3K/Akt. OPN neutralization significantly reduces NASH fibrosis, reinforcing the potential utility of targeting OPN in the treatment of patients with advanced NASH.

Topics: Animals; Cell Line; Cells, Cultured; Gene Deletion; Hepatocytes; Leptin; Liver; Liver Cirrhosis; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Osteopontin; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Up-Regulation

Hypermetabolism in cirrhosis is associated with a high risk of complications and mortality. However, studies about underlying mechanisms are usually focussed on isolated potential determinants and specific etiologies, with contradictory results. We aimed at investigating differences in nutrition, metabolic hormones, and hepatic function between hypermetabolic and nonhypermetabolic men with cirrhosis of the liver.. We prospectively enrolled 48 male cirrhotic inpatients. We evaluated their resting energy expenditure (REE) and substrate utilization by indirect calorimetry, body composition by dual-energy X-ray absorptiometry, liver function, and levels of major hormones involved in energy metabolism by serum sample tests. Patients with ascites, specific metabolic disturbances, and hepatocellular carcinoma were excluded.. REE and REE adjusted per fat-free mass (FFM) were significantly increased in cirrhotic patients. Overall, 58.3% of cirrhotic patients were classified as hypermetabolic. Groups did not differ significantly in age, etiology of cirrhosis, liver function, presence of ascites, use of diuretics, β-blockers, or presence of transjugular intrahepatic portosystemic shunts. Hypermetabolic cirrhotic patients had lower weight, BMI (P<0.05), nonprotein respiratory quotient (P<0.01), leptin (P<0.05), and leptin adjusted per fat mass (FM) (P<0.05), but higher FFM% (P<0.05) and insulin resistance [homeostatic model assessment-insulin resistance (HOMA-IR)] (P<0.05). Only HOMA-IR, leptin/FM, and FFM% were independently related to the presence of hypermetabolism.. Hypermetabolic cirrhotic men are characterized by lower weight, higher FFM%, insulin resistance, and lower leptin/FM when compared with nonhypermetabolic men. HOMA-IR, FFM%, and leptin/FM were independently associated with hypermetabolism, and may serve as easily detectable markers of this condition in daily clinical practice.

Topics: Absorptiometry, Photon; Adult; Basal Metabolism; Biomarkers; Blood Glucose; Body Composition; Body Weight; Calorimetry, Indirect; Case-Control Studies; Humans; Insulin; Insulin Resistance; Leptin; Liver Cirrhosis; Liver Function Tests; Male; Metabolic Diseases; Middle Aged; Nutritional Status; Predictive Value of Tests; Prospective Studies; Rest

Trans-chalcone is the precursor molecule to flavonoids and possesses antioxidant and anti-inflammatory properties. This study aimed to evaluate the effects of trans-chalcone on atheroma plaque formation and the relevant biochemical parameters in high cholesterol diet (HCD)-fed NMRI mice.. Fifty male NMRI mice were divided into 5 groups (n=10 per group): control (received a normal diet); HCD (received an additional 2% cholesterol for 18 weeks); sham (received a HCD for 12 weeks and were then shifted to a normal diet and trans-chalcone vehicle (sunflower oil) for 6 weeks), and two experimental groups (received a HCD for 12 weeks and were then shifted to a normal diet and either 12mg/kg or 24mg/kg trans-chalcone for 6 weeks).. After 12 weeks, HCD-induced atheroma plaques were observed by hematoxylin and eosin staining of aortic sections. At the end of experiment, the following factors had significantly increased in the HCD group: body weight, insulin resistance, and serum levels of triglycerides, total-cholesterol, glucose, insulin, leptin, liver enzymes (AST and ALT), malondialdehyde and direct bilirubin. The serum levels of high-density lipoprotein cholesterol, adiponectin, superoxide dismutase, and glutathione had considerably decreased. Histologic analysis of liver sections indicated hepatic fibrosis and steatosis. Treatment by both doses of trans-chalcone, particularly the 24mg/kg dose, significantly attenuated these alterations.. Administration of trans-chalcone improved the consequences of atheroma plaque formation and liver fibrosis via increased expression of adiponectin, generation of higher levels of antioxidant enzymes, as well as modulation of serum leptin and lipid profiles.

Topics: Adiponectin; Animals; Bilirubin; Blood Glucose; Body Weight; Chalcone; Cholesterol; Cholesterol, HDL; Fatty Liver; Gene Expression; Glutathione; Insulin; Insulin Resistance; Leptin; Liver Cirrhosis; Male; Malondialdehyde; Mice; Plaque, Atherosclerotic; Superoxide Dismutase; Triglycerides

Malnutrition is a leading cause of morbidity and mortality in cirrhosis. There is no consensus as to the optimal approach for identifying malnutrition in end-stage liver disease. The aim of this study was to measure biochemical, serologic, hormonal, radiographic, and anthropometric features in a cohort of hospitalized cirrhotic patients to characterize biomarkers for identification of malnutrition.. In this prospective observational cohort study, 52 hospitalized cirrhotic patients were classified as malnourished (42.3%) or nourished (57.7%) based on mid-arm muscle circumference < 23 cm and dominant handgrip strength < 30 kg. Anthropometric measurements were obtained. Appetite was assessed using the Simplified Nutrition Appetite Questionnaire (SNAQ) score. Fasting levels of serum adipokines, cytokines, and hormones were determined using Luminex assays. Logistic regression analysis was used to determine features independently associated with malnutrition.. Subjects with and without malnutrition differed in several key features of metabolic phenotype including wet and dry BMI, skeletal muscle index, visceral fat index and HOMA-IR. Serum leptin levels were lower and INR was higher in malnourished subjects. Serum leptin was significantly correlated with HOMA-IR, wet and dry BMI, mid-arm muscle circumference, skeletal muscle index, and visceral fat index. Logistic regression analysis revealed that INR and log-transformed leptin were independently associated with malnutrition.. Low serum leptin and elevated INR are associated with malnutrition in hospitalized patients with end-stage liver disease.

Topics: Adipokines; Biomarkers; Cytokines; Female; Hormones; Humans; International Normalized Ratio; Leptin; Liver Cirrhosis; Male; Malnutrition; Middle Aged; Prospective Studies

Micro-RNAs (miRNAs) are involved in regulation of the incidence and development of several hepatic diseases. Thus manipulating miRNAs may be a promising therapeutic strategy against these entities. In this study hepatic stellate cells (HSCs) were transfected with hsa-miR-9 or anti-hsa-miR-9, treated with tetramethylpyrazine (TMP), or subjected to treatment with TMP and hsa-miR-9 transfection (combined treatment group). Then, real-time polymerase chain reaction (PCR) was performed to measure mRNA levels of hsa-miR-9. Expression of hsa-miR-9 was highest in the combination treatment group compared with other groups, and significantly higher than TMP-treated and hsa-miR-9-transfected groups (both p<0.05). The anti-hsa-miR-9-transfected group expressed the lowest mRNA level of hsa-miR-9 with marked decrease versus control (p<0.05). Downstream factors that may be affected by miR-9 such as leptin, α-smooth muscle actin (SMA), and collagen I, as well as phosphorylation levels of Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) were investigated at the protein level. All these factors were regulated contrariwise to expression trends of hsa-miR-9, showing the lowest level in the combination treatment group and highest level in anti-hsa-miR-9-transfected group. These results suggest that both transfection of hsa-miR-9 and TMP can lead to upregulated endogenous expression of hsa-miR-9, inhibit activation of JAK1/STAT3 signal pathway induced by leptin, and lead to reduction of α-SMA and collagen I-thus impeding activation of HSC.

Topics: Actins; Collagen Type I; Gene Expression Regulation; Hepatic Stellate Cells; Humans; Janus Kinase 1; Leptin; Ligusticum; Liver Cirrhosis; MicroRNAs; Phosphorylation; Phytotherapy; Plant Extracts; Pyrazines; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Transfection; Up-Regulation

Adipocytokines play an important role in lipid metabolism and liver disease progression. However, the interactions between hepatitis B virus (HBV) infection and adipocytokines remain largely unknown.. To investigate the association of HBV infection with adipocytokines in HBV-infected and noninfected subjects. In addition, the impact of adipocytokines on serum HBV DNA, HBsAg levels and liver fibrosis stage was also examined.. A case-control analysis of patients with and without chronic HBV infection was performed. The HBV group consisted of 187 patients with chronic HBV infection, and the control group consisted of 184 age-, gender- and body mass index-matched subjects without HBV infection. Fasting blood glucose, lipid profiles, adiponectin, leptin and visfatin levels were compared between the two groups. APRI and FIB-4 were calculated to estimate the severity of liver fibrosis.. Most of the enrolled subjects had lower ALT levels [228 (57.7%) ALT < ULN] and milder hepatic fibrosis [381 (96.5%) APRI < 0.7; 307 (77.7%) FIB4 < 1.45]. The HBV group had significantly higher serum adiponectin and visfatin but lower leptin levels than the control group. This difference remained significant after adjustment for age, sex, BMI and ALT levels (p < 0.05). Serum adiponectin, leptin and visfatin levels were significantly associated with serum HBsAg and HBV DNA levels (p < 0.05). In addition, a higher serum adiponectin level was associated with advanced liver fibrosis in elder male HBeAg-negative patients.. Patients with chronic HBV infection have significantly higher serum adiponectin and visfatin but lower leptin levels than healthy controls. Serum adipocytokine levels independently correlate with HBV viremia, HBsAg levels and liver fibrosis stages.

Topics: Adiponectin; Adult; Age Factors; Alanine Transaminase; Aspartate Aminotransferases; Case-Control Studies; Cohort Studies; DNA, Viral; Female; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Platelet Count; Severity of Illness Index; Sex Factors

Apoptosis inhibitor of macrophage (AIM) and adipocytokines are involved in the metabolic syndrome, which has been putatively associated with the progression of chronic hepatitis C (CHC). However, the association between these cytokines and CHC is not fully elucidated. The aim of this study is to test whether serum levels of AIM and adipocytokines are associated with histological features, homeostasis model assessment-insulin resistance index (HOMA-IR), or whole body insulin sensitivity index (WBISI) in CHC patients.. Serum samples were obtained from 77 patients with biopsy-proven CHC. In 39 patients without overt diabetes mellitus, a 75 g oral glucose tolerance test (OGTT) was performed and HOMA-IR and WBISI were calculated.. A serum AIM level of ≥ 1.2 μg/ml was independently associated with advanced hepatic fibrosis (F2 or F3) (odds ratio [OR], 5.612; 95% confidence interval [CI], 1.103-28.563; P = 0.038) based on a multivariate analysis, but there was no significant association between AIM and hepatic steatosis or inflammation. Furthermore, a serum leptin level of ≥ 8.6 ng/ml was independently associated with the presence of hepatic steatosis (≥ 5%) (OR, 6.195; 95% CI, 1.409-27.240; P = 0.016), but not hepatic fibrosis or inflammation. No relationship was observed between levels of adiponectin or resistin and hepatic histological parameters based on a multivariate analysis. Although serum levels of leptin, resistin, and adiponectin were significantly correlated with HOMA-IR and WBISI, there was no significant relationship between serum AIM levels and HOMA-IR or WBISI, respectively.. High serum levels of AIM in CHC patients are potentially related to advanced hepatic fibrosis. AIM and adipocytokines are possibly associated with pathological changes via a different mechanism.

Topics: Adiponectin; Adult; Age Factors; Aged; Alanine Transaminase; Biomarkers; Fatty Liver; Female; gamma-Glutamyltransferase; Glucose Tolerance Test; Hepatitis C, Chronic; Homeostasis; Humans; Hyaluronic Acid; Insulin Resistance; Leptin; Liver Cirrhosis; Male; Middle Aged; Platelet Count; Receptors, Scavenger; Resistin; Serum Albumin; Severity of Illness Index

Non-alcoholic steatohepatitis (NASH) is a major risk factor for hepatic fibrogenesis. NASH is often found in diabetic patients with hyperglycemia. Hyperglycemia induces non-enzymatic glycation of proteins, yielding advanced glycation end-products (AGEs). Effects of AGEs are mainly mediated by two categories of cytoplasmic membrane receptors. Receptor for AGEs (RAGE) is associated with increased oxidative stress and inflammation, whereas AGE receptor-1 (AGE-R1) is involved in detoxification and clearance of AGEs. Activation of hepatic stellate cells (HSC) is crucial to the development of hepatic fibrosis. We recently reported that AGEs stimulated HSC activation likely by inhibiting gene expression of AGE-R1 and inducing gene expression of RAGE in HSC, which were eliminated by the antioxidant curcumin. This study is to test our hypothesis that curcumin eliminates the effects of AGEs on the divergent regulation of the two receptors of AGEs in HSC by interrupting the AGE-caused activation of leptin signaling, leading to the inhibition of HSC activation. We observed herein that AGEs activated leptin signaling by inducing gene expression of leptin and its receptor in HSC. Like AGEs, leptin differentially regulated gene expression of RAGE and AGE-R1. Curcumin eliminated the effects of AGEs in HSC by interrupting leptin signaling and activating transcription factor NF-E2 p45-related factor 2 (Nrf2), leading to the elevation of cellular glutathione and the attenuation of oxidative stress. In conclusions, curcumin eliminated the effects of AGEs on the divergent regulation of gene expression of RAGE and AGE-R1 in HSC by interrupting the AGE-caused activation of leptin signaling, leading to the inhibition of HSC activation.

Topics: Animals; Antineoplastic Agents; Cells, Cultured; Chromones; Curcuma; Curcumin; Gene Expression Regulation; Glycation End Products, Advanced; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Morpholines; Plant Extracts; Rats; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Receptors, Leptin; Tyrphostins

Hepatic stellate cell (HSC) activation is a crucial step in the development of liver fibrosis. Peroxisome-proliferator activated receptor γ (PPARγ) exerts a key role in the inhibition of HSC activation. Leptin reduces PPARγ expression in HSCs and plays a unique role in promoting liver fibrosis. The present studies aimed to investigate the mechanisms underlying leptin regulation of PPARγ1 (a major subtype of PPARγ) in HSCs in vivo and in vitro. Results revealed a leptin response region in mouse PPARγ1 promoter and indicated that the region included a GATA binding protein binding site around position -2323. GATA binding protein-2 (GATA-2) could bind to the site and inhibit PPARγ1 promoter activity in HSCs. Leptin induced GATA-2 expression in HSCs in vitro and in vivo. GATA-2 mediated leptin inhibition of PPARγ1 expression by its binding site in PPARγ1 promoter in HSCs and GATA-2 promoted HSC activation. Leptin upregulated GATA-2 expression through β-catenin and sonic hedgehog pathways in HSCs. Leptin-induced increase in GATA-2 was accompanied by the decrease in PPARγ expression in HSCs and by the increase in the activated HSC number and liver fibrosis in vivo. Our data might suggest a possible new explanation for the promotion effect of leptin on liver fibrogenesis.

Topics: Animals; beta Catenin; Binding Sites; Blotting, Western; Cells, Cultured; GATA2 Transcription Factor; Gene Expression; Hedgehog Proteins; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Mice, Inbred C57BL; Mice, Obese; PPAR gamma; Promoter Regions, Genetic; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

This study evaluated the possible antifibrotic effect of pentoxifylline on experimentally induced schistosomal hepatic fibrosis and its effect on serum leptin and transforming growth factor-β1 levels as possible antifibrotic mechanisms in correlation with the hepatic fibrosis indices. A total of ninety clean laboratories bred, males Swiss, albino mice were included, of which ten mice served as a control non-infected, non-treated group and sacrificed at one time. Eighty mice, each was subcutaneously infected with 50 Schistosoma mansoni cercariae and classified into groups: GI (infected & non-treated), GII (infected & treated with Mirazid), GIII (infected & treated with Pentoxifylline) and GIV (infected & treated with a combination of Mirazid and Pentoxifylline). Each group was further subdivided into 2 subgroups; subgroup 'a' which started treatment at 6th week post-infection (P.I.) and sacrificed at the end of 9th week P.I and subgroup 'b' which started treatment at 14th week P.I and sacrificed at the end of 17th week P.I. The efficacy of the treatment was assessed by histopathological examination of the liver with measurement of granuloma sizes, estimation of hydroxyproline content in the liver, and assessment of serum levels of leptin and transforming growth factor- β1 (TGF-β1).Mirazid (MZD) caused significant reductions in granuloma sizes and hepatic hydroxyproline content and caused non-significant reductions in serum levels of leptinand transforming growth factor- β1 t 9th & 17t hweeks P.II(GIII. Pentoxifylline (PTX) caused significant reductions in granuloma sizes, hepatic hydroxyproline, and serum levels of leptin and transforming growth factor- β1 t the 9"th& 17kt weeks P.II (GIII. While combined therapy of both MZD & PTX in GIIVcaused more reductions in granuloma sizes, hepatic hydroxyproline, and serum levels of leptin and TGF- β1 t the 9th & 17th weeks P.IIwhen compared to the other groups.

Topics: Animals; Female; Free Radical Scavengers; Leptin; Liver Cirrhosis; Male; Mice; Pentoxifylline; Schistosomiasis mansoni; Transforming Growth Factor beta1

The detection and diagnosis of hepatocellular carcinoma (HCC) at an early stage may significantly affect the prognosis of HCC patients. Thus, it is necessary to always identify novel putative markers for improving diagnosis. Hepatocarcinogenesis correlates with pathological hepatic angiogenesis. However, each tumor-induced angio-genetic process is influenced by the microenvironment through several pro- and anti-angiogenic factors released from tumor cells, tumor-associated inflammatory cells and/or from the extracellular matrix, and modulated by various signal pathways. In this study, we evaluated the profiling of angiogenic factors using Bio-Plex Pro™ Human Cancer Biomarker Panel 1, a 16-plex magnetic bead-based assay, in sera of patients with chronic hepatitis C (CHC) virus, liver cirrhosis (LC) and HCC. Our results demonstrated: i) high levels of hepatocyte growth factor (HGF) and prolactin only in LC and HCC patients, ii) high levels of soluble human epidermal growth factor receptor‑2 (sHER-2/neu; ErbB-2), sIL-6Ra, leptin (LEP) and platelet endothelial cell adhesion molecule‑1 (PECAM-1) in CHC, LC and HCC patients and iii) that sIL-6R correlated with the fibrosis stage in CHC patients, with Child‑Pugh score in those patients with LC and with tumor size in those patients with HCC, confirming that this protein may be used as a predictor of liver damage and of inflammatory process leading to fibrosis, cirrhosis, and subsequently to cancer. Moreover, an interactomic study conducted using the Ingenuity Pathway Analysis (IPA) software proved the existence of a correlation between 5 significant proteins [ErbB-2, sIL-6Ra, prolactin (PRL), HGF and LEP] which are involved in the same metabolic pathways.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Hepatocellular; Case-Control Studies; Female; Hepatitis C, Chronic; Hepatocyte Growth Factor; Humans; Interleukin-6 Receptor alpha Subunit; Leptin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Platelet Endothelial Cell Adhesion Molecule-1; Prognosis; Prolactin; Receptor, ErbB-2

To investigate the effect of plumbagin on the expression of TNF-alpha and PDGF-BB in human hepatic stellate cells (HSC-LX2) activated by Leptin.. HSC-LX2 were cultured in vitro and stimulated by Leptin for 24 hours then treated with different concentrations of plumbagin for 24 hours, the expressions of TNF-alpha mRNA and PDGF-BB mRNA were determined by Realtime quantitative PCR, the protein expressions of TNF-alpha and PDGF-BB were determined-by Western blotting.. The expressions of TNF-alpha mRNA and PDGF-BB mRNA of treatment groups were significantly reduced, especially in high dose group (P < 0.01), and Western blotting analyses revealed similar trends in protein expression.. Plumbagin may prevent the formation of hepatic fibrosis and its mechanism may be related to decreasing the level of mRNA of TNF-alpha and PDGF-BB and the protein of PDGF-BB.

Topics: Becaplermin; Cells, Cultured; Gene Expression Regulation; Hepatic Stellate Cells; Humans; Leptin; Liver Cirrhosis; Naphthoquinones; Plumbaginaceae; Polymerase Chain Reaction; Proto-Oncogene Proteins c-sis; RNA, Messenger; Tumor Necrosis Factor-alpha

We investigated possible involvements of bile acids (BA) and leptin in hepatogenous insulin resistance being present in up to 90% of cirrhotic patients.. Blood was analysed in 10 cirrhotic patients (8m/2f, 48 ± 10.4 yrs) and 10 controls (8m/2f, 43 ± 9.3 yrs) after oral nutrition and during 1 h of parenteral feeding. In patients, leptin was additionally analysed from mesenteric and arterial blood.. Cirrhosis patients showed typical signs of hepatogenous insulin resistance (hyperinsulinaemia, normoglycaemia, hyperglucagonaemia). Both fasting BA (r = .714, p = 0.047) and fasting leptin (r = .867, p = 0.001) correlated to HOMA and predicted insulin response after oral feeding (R²adj = .783, p = 0.002). But during parenteral nutrition only leptin predicted insulin response (p = 0.005). The prandial glucose response was negatively correlated to the BA increase after oral nutrition (r = -.733, p = 0.028) and to the change in leptin during parenteral nutrition (r = -.738, p = 0.037) pointing towards a nutritional route-dependent positive impact on glucose tolerance of both substances. Prandial glucagon response was correlated to BA under both feeding conditions (p < 0.05). We found no relevant intestinal release of leptin during fasting or feeding conditions.. Our results suggest a substantial involvement of BA and leptin by improving postprandial glucose tolerance related to liver cirrhosis.

Topics: Adipose Tissue, White; Adult; Bile Acids and Salts; Female; Glucagon; Glucose; Humans; Hyperglycemia; Insulin Resistance; Intestinal Mucosa; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged; Parenteral Nutrition; Postprandial Period

Ghrelin, leptin, and insulin concentrations are involved in the control of food intake and they seem to be associated with anorexia-cachexia in cirrhotic patients. The present study aimed to investigate the relationship between the nutritional status and fasting ghrelin, leptin and insulin concentrations in pediatric cirrhotic patients.. Thirty-nine patients with cirrhosis and 39 healthy controls aged 0-15 years matched by sex and age were enrolled. Severity of liver disease was assessed by Child-Pugh classification, and Pediatric for End Stage Liver Disease (PELD) or Model for End-stage Liver Disease (MELD) scores. Blood samples were collected from patients and controls to assay total ghrelin, acyl ghrelin, leptin and insulin by using a commercial ELISA kit. Anthropometry parameters used were standard deviation score of height-for-age and triceps skinfold thickness-for-age ratio. A multiple linear regression analysis was used to determine the correlation between dependent and independent variables.. Acyl ghrelin was significantly lower in cirrhotic patients than in controls [142 (93-278) pg/mL vs 275 (208-481) pg/mL, P=0.001]. After multiple linear regression analysis, total ghrelin and acyl ghrelin showed an inverse correlation with age; acyl ghrelin was associated with the severity of cirrhosis and des-acyl ghrelin with PELD or MELD scores ≥15. Leptin was positively correlated with gender and anthropometric parameters. Insulin was not associated with any variable.. Low acyl ghrelin and high des-acyl ghrelin concentrations were associated with cirrhosis severity, whereas low leptin concentration was associated with undernourishment in children and adolescents with cirrhosis.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Fasting; Female; Ghrelin; Humans; Infant; Infant, Newborn; Insulin; Leptin; Liver Cirrhosis; Male; Nutritional Status; Severity of Illness Index

Leptin, the adipocyte-derived hormone, plays an unique role in promoting liver fibrosis. Hepatic stellate cell (HSC) activation is the key step in liver fibrogenesis and sterol regulatory element binding protein-1c (SREBP-1c, a pivotal transcription factor for adipocyte differentiation) exerts a critical function in inhibition of HSC activation. Stat3 pathway is the main pathway induced by leptin and its role in liver fibrogenesis is controversial. Our previous results demonstrated the inhibitory effect of leptin on SREBP-1c expression in HSCs. The present study aimed to explore the role of Stat3 pathway in leptin-induced liver fibrogenesis in mouse model, focusing on examining the effect of leptin-induced Stat3 pathway on SREBP-1c expression in HSCs in vitro and in vivo. Results suggested that Stat3 pathway mediated the promotional role of leptin in liver fibrosis in mouse and was involved in leptin inhibition of SREBP-1c expression in HSCs. Leptin-induced Stat3 activation was, at least partially, ERK pathway-dependent in cultured HSCs and was correlated positively with β-catenin activity and negatively with liver X receptor α expression and activity which influenced SREBP-1c expression in HSCs. The decrease in SREBP-1c expression by leptin-induced Stat3 pathway led to the increase in the marker for HSC activation and in α1(I) collagen expression in HSCs. In summary, the effect of leptin-induced Stat3 pathway on SREBP-1c expression in HSCs might contribute to the role of leptin in liver fibrosis in mouse, thus advancing understanding of the mechanisms of liver fibrogenesis associated with leptin.

Topics: Animals; beta Catenin; DNA-Binding Proteins; Gene Expression Regulation; Hepatic Stellate Cells; Humans; Leptin; Liver Cirrhosis; MAP Kinase Signaling System; Mice; Promoter Regions, Genetic; Rats; STAT3 Transcription Factor; Sterol Regulatory Element Binding Protein 1

Liver fibrosis is commonly associated with obesity and most obese patients develop hyperleptinaemia. The adipocytokine leptin has a unique role in the development of liver fibrosis. Activation of hepatic stellate cells (HSCs) is a key step in hepatic fibrogenesis and sterol regulatory element-binding protein-1c (SREBP-1c) can inhibit HSC activation. We have shown that leptin strongly inhibits SREBP-1c expression in rat HSCs. Hence, we aimed to clarify whether the β-catenin pathway, the crucial negative regulator of adipocyte differentiation, mediates the effects of leptin on SREBP-1c expression in HSCs and in mouse liver fibrosis.. HSCs were prepared from rats and mice. Gene expressions were analysed by real-time PCR, Western blot analysis, immunostaining and transient transfection assays.. Leptin increased β-catenin protein but not mRNA levels in cultured HSCs. Leptin induced phosphorylation of glycogen synthase kinase-3β at Ser(9) and subsequent stabilization of β-catenin protein was mediated, at least in part, by ERK and p38 MAPK pathways. The leptin-induced β-catenin pathway reduced SREBP-1c expression and activity but did not affect protein levels of key regulators controlling SREBP-1c activity, and was not involved in leptin inhibition of liver X receptor α. In a mouse model of liver injury, the β-catenin pathway was shown to be involved in leptin-induced liver fibrosis.. The β-catenin pathway contributes to leptin regulation of SREBP-1c expression in HSCs and leptin-induced liver fibrosis in mice. These results have potential implications for clarifying the mechanisms of liver fibrogenesis associated with elevated leptin levels.

Topics: Animals; beta Catenin; Blotting, Western; Disease Models, Animal; Gene Expression Regulation; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sterol Regulatory Element Binding Protein 1

Leptin and adiponectin have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). However, the usefulness of adipocytokines as a screening tool for nonalcoholic steatohepatitis (NASH) and fibrosis could not be evaluated in the general population due to the invasive nature of liver biopsy. The aim was to evaluate the association between adipocytokines and presumed liver injury in the general population using noninvasive biomarkers.. A cross-sectional study of 375 individuals, sampled from the National Health Survey was conducted. The exclusion criterion was any known secondary etiology for liver disease. Anthropometrics, serum leptin, adiponectin, insulin, lipids, and FibroMax were measured.. Three hundred and thirty-eight individuals met the inclusion criteria and had valid FibroMax. Fibrosis diagnosed by the FibroTest was found in 25.7% of the patients, of whom 12.8% had significant fibrosis. Steatohepatitis was diagnosed by the NASH test in 0.9% and borderline NASH in 31.4% of the patients. Adiponectin was an independent negative correlate of borderline NASH [odds ratio (OR): 0.92; 95% confidence interval (CI): 0.86-0.98/1 µg/ml] together with high-density lipoprotein, and leptin was a positive correlate (OR: 1.03; CI: 1.01-1.06/1 ng/ml), together with abdominal obesity, serum triglycerides, and HbA1C. The OR for borderline NASH was 20.7 (CI: 7.5-57.5) when both high leptin (upper quartile) and suboptimal adiponectin were present, adjusting for age and sex. The FibroTest was not associated with leptin and adiponectin. The strongest predictors for fibrosis were age, sex, abdominal obesity, and insulin.. Low adiponectin and high leptin and the combination of both have a strong independent association with presumed early-stage NASH. However, early-stage fibrosis cannot be predicted by these adipocytokines.

Topics: Adipokines; Adiponectin; Adult; Aged; Biomarkers; Cross-Sectional Studies; Early Diagnosis; Epidemiologic Methods; Fatty Liver; Female; Humans; Insulin; Leptin; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Sex Distribution

It is well established that hepatocellular carcinoma (HCC) develops in a multistep process, from chronic hepatitis, cirrhosis to HCC. Adipose tissue is not simply an energy storage organ but also a secretory organ, producing a variety of bioactive molecules known as adipokines, including adiponectin and leptin. Hyaluronic acid (HA) is an extracellular matrix protein, often associated with a variety of human cancers. Our retrospective study determines serum levels of adiponectin, leptin, and HA in HCC of cirrhotic and noncirrhotic patients and compares these levels to patients with cirrhosis and normal subjects. Noncirrhotic HCC (n = 19), cirrhotic HCC (n = 50), cirrhosis (n = 36) patients and twenty one age-, sex-, and body mass index (BMI)-matched normal healthy controls were subjected in the present study. Serum adiponectin, leptin, and HA levels were determined using enzyme-linked immunosorbent assay technique. Levels of serum adiponectin were significantly higher in the cirrhosis and cirrhotic HCC groups than in the normal subjects, whereas serum HA levels were found to significantly increase in all three patients groups. The elevation of serum leptin in our HCC patients, regardless of being cirrhotic or noncirrhotic, but not in the patients with cirrhosis, may shed some light on the significance of serum leptin level in HCC. Further studies are recommended to evaluate the prognostic value of serum leptin level in HCC.

Topics: Adiponectin; Adult; Aged; Carcinoma, Hepatocellular; Case-Control Studies; Female; Humans; Hyaluronic Acid; Leptin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies

Decompressing the portal hypertension by inserting a transjugular intrahepatic porto-systemic shunt (TIPS) in undernourished liver cirrhosis patients results in gains in body weight. It is important to understand whether this reflects an advantageous or unfavourable shift in nutrition status. This to some extent can be judged from the changes in the patients' adipokine patterns. We, therefore, examined the circulating levels of the most important adipokines before and after the TIPS procedure.. Twenty-five liver cirrhosis patients were examined before TIPS insertion and followed for six months after the procedure. Their body composition was determined by the bioimpedance technique. The serum concentrations of adiponectin, retinol binding protein 4 (RBP4), and leptin were measured.. The TIPS procedure induced a 12% increase in body cell mass (P = 0.03) but did not change the body fat mass. At six months, serum adiponectin was increased by 60% (mean ± SD, 10.7 ± 6.1 vs. 16.9 ± 8.9 mg/L; P = 0.001), serum RBP4 was decreased by 45% (28.6 ± 20.0 vs. 16.3 ± 9.6 mg/L; P = 0.01), and the leptin levels remained unchanged.. The TIPS-related tissue build up was accompanied by increased adiponectin and decreased RBP4. Such changes are associated with an anabolic condition where the adipose tissue possesses residual capacity for energy storage. TIPS, therefore, can be considered to be nutritionally beneficial to cirrhosis patients.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adult; Aged; Body Composition; Electric Impedance; Female; Humans; Hypertension, Portal; Leptin; Liver Cirrhosis; Male; Malnutrition; Middle Aged; Nutritional Status; Portasystemic Shunt, Transjugular Intrahepatic; Retinol-Binding Proteins, Plasma

Although bacterial endotoxin, such as lipopolysaccharide (LPS), plays a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH), detailed mechanisms of this pathogenesis remain unclear. Here, we demonstrate that upregulation of CD14 by leptin-mediated signaling is critical to hyperreactivity against endotoxin during NASH progression. Upregulation of CD14 in Kupffer cells and hyperreactivity against low-dose LPS were observed in high-fat diet (HFD)-induced steatosis mice, but not chow-fed-control mice. Hyperresponsivity against low-dose LPS led to accelerated NASH progression, including liver inflammation and fibrosis. Administering leptin in chow-fed mice caused increased hepatic expression of CD14 via STAT3 signaling, resulting in hyperreactivity against low-dose LPS without steatosis. In contrast, a marked decrease in hepatic CD14 expression was observed in leptin-deficient ob/ob mice, despite severe steatosis. Our results indicate that obesity-induced leptin plays a crucial role in NASH progression via enhanced responsivity to endotoxin, and we propose a mechanism of bacteria-mediated progression of NASH.

Topics: Alanine Transaminase; Animals; Cell Line; Cytokines; Diet, High-Fat; Fatty Liver; Gene Expression; Hepatitis, Animal; Humans; Leptin; Lipopolysaccharide Receptors; Lipopolysaccharides; Liver Cirrhosis; Liver Cirrhosis, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Signal Transduction; STAT3 Transcription Factor; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Hyaluronan, leptin, laminin and collagen IV have been used extensively for the assessment of liver fibrosis. The aim of this study was to assay these markers in the peripheral and hepatic vein blood of primary biliary cirrhosis (PBC) patients and to study their ability to discriminate early from advanced disease.. Sera from 62 PBC patients were compared to 60 controls, 44 chronic Hepatitis C, 38 hepatocellular carcinoma and 34 viral cirrhosis patients. Serum from the hepatic vein of 15 cirrhotic PBC patients and 17 patients with viral cirrhosis was also assayed.. All disease groups had significantly increased levels of hyaluronan and collagen IV, compared to controls, while laminin was significantly increased only in viral cirrhosis. Hyaluronan levels were statistically different between early (54.5 ng/ml; 95%CI 27.3-426.9) and late PBC (154.5 ng/ml; 95%CI 55.3-764.4, p<0.05). The area under the curve (AUC) for the identification of late PBC was 0.74 for hyaluronan, 0.63 for leptin, 0.59 for laminin and 0.70 for collagen IV. Hyaluronan had high sensitivity and NPV in identifying late stages of PBC (96% and 90%, respectively). Short term UDCA had no effect on these markers.. No single measurement can differentiate between advanced and early fibrosis in PBC. However serum hyaluronan is a promising single serum marker for longitudinal studies in PBC.

Topics: Adjuvants, Immunologic; Aged; Algorithms; Biomarkers; Carcinoma, Hepatocellular; Case-Control Studies; Collagen Type IV; Diagnosis, Differential; Early Diagnosis; Female; Hepatitis C, Chronic; Humans; Hyaluronic Acid; Laminin; Leptin; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Neoplasms; Male; Middle Aged; Predictive Value of Tests; Sensitivity and Specificity

The aim of this prospective study was too asses the frequency and clinical significance of metabolic syndrome (MS), insulin resistance (IR) and hepatic steatosis in 114 patients with chronic hepatitis C (HCV) genotype 1. MS was found in 47% and IR in 50% of the cases. Diagnosis of IR in patients without MC and marked fibrosis supported the role of HCV in the development of metabolic abnormalities. Hepatic steatosis was found in 38% of the patients and the degree of steatosis significantly correlated with that of fibrosis. Obesity, IR, steatosis and liver cirrhosis were independent negative predictors of the response to the treatment with peginterferon alpha and ribavirin.

Topics: Adult; Antiviral Agents; Fatty Liver; Female; Genome, Viral; Hepacivirus; Hepatitis C, Chronic; Hepatocytes; Humans; Insulin Resistance; Interferon alpha-2; Interferon-alpha; Leptin; Liver Cirrhosis; Male; Metabolic Syndrome; Middle Aged; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Ribavirin; Severity of Illness Index; Treatment Outcome

The relationship between metabolic abnormalities of trace elements and insulin resistance has been established. Recent studies have revealed that insulin resistance is associated with autoimmune responses. The purpose of this study was to examine the correlation between zinc or copper metabolism and insulin resistance in patients with primary biliary cirrhosis (PBC). Sixteen patients with PBC were divided into two groups: early and advanced stage disease. The overall value of the homeostasis model assessment of insulin resistance (HOMA-IR) in patients with advanced stage PBC was significantly higher than that in patients with early stage PBC, although the mean value in advanced stage PBC was significantly lower than that in hepatitis C virus (HCV)-related liver cirrhosis. There was an inverse correlation between serum zinc concentrations and HOMA-IR values in patients with PBC, while we found no correlation between serum copper levels and HOMA-IR values. HOMA-IR values were inversely associated with peripheral platelet counts, indicating the relationship between insulin resistance and hepatic fibrosis. These results suggest that zinc deficiency plays important roles of insulin resistance and subsequent hepatic fibrosis in patients with PBC, although insulin resistance in advanced stage PBC was significantly milder than that in HCV-related liver cirrhosis.

Topics: Adult; Aged; Autoantibodies; Autoimmune Diseases; Biomarkers; Copper; Deuteroporphyrins; Disease Progression; Female; Hepatitis C, Chronic; Homeostasis; Humans; Imines; Insulin Resistance; Japan; Leptin; Liver; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Function Tests; Male; Middle Aged; Mitochondria, Liver; Platelet Count; Zinc

Mechanisms of liver fibrosis are complex and varied. Among them, metabolic factors are particularly important in the development of fibrosis associated with nonalcoholic steatohepatitis (NASH). These factors are some of the "multiple parallel hits" responsible for liver damage during NASH. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Major profibrogenic protagonists, such as hepatic stellate cells and Kupffer cells, are activated by insulin resistance, apoptosis and local inflammation. Relations between steatosis, insulin resistance and fibrosis are complex. Initially, simple steatosis may be a way to store deleterious free fatty acid in neutral triglycerides. If the lipid storage threshold is exceeded, steatosis may become associated with lipotoxicity. Similarly, interindividual variations of adipose tissue expandability might explain various phenotypes, ranging from "metabolically obese patients with normal weight" to "metabolically normal morbidly obese patients". The metabolic abnormalities in subcutaneous and visceral adipose tissue are insulin resistance and low-grade inflammation, which are associated with increased release of free fatty acid flux and changes in adipocytokines production such as leptin, adiponectin and interleukin 6. The nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and the endocannabinoid system might have important roles in liver fibrogenesis and are potential therapeutic targets. Finally, with the development of new molecular tools, gut microbiota has been recently identified for its pleiotropic functions, including metabolism regulation. Better knowledge of these mechanisms should lead to new strategies for the treatment of metabolic factors that play a key role in liver injuries.

Topics: Adipokines; Adiponectin; Biomarkers; Body Mass Index; Cannabinoid Receptor Modulators; Fatty Liver; Hepatic Stellate Cells; Humans; Interleukin-6; Kupffer Cells; Leptin; Liver Cirrhosis; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; PPAR gamma; Risk Factors

Adiponectin is protective against hepatic fibrosis, whereas leptin promotes fibrosis. In HSCs (hepatic stellate cells), leptin signals via a JAK2 (Janus kinase 2)/STAT3 (signal transducer and activator of transcription 3) pathway, producing effects that enhance ECM (extracellular matrix) deposition. SOCS-3 (suppressor of cytokine signalling-3) and PTP1B (protein tyrosine phosphatase 1B) are both negative regulators of JAK/STAT signalling, and recent studies have demonstrated a role for adiponectin in regulating SOCS-3 expression. In the present study we investigate mechanisms whereby adiponectin dampens leptin signalling and prevents excess ECM production. We treated culture-activated rat HSCs with recombinant adiponectin, leptin, both or neither, and also treated adiponectin knockout (Ad-/-) and wild-type mice with leptin and/or carbon tetrachloride (CCl4) or saline. We analyse JAK2 and Ob-Rb (long form of the leptin receptor) phosphorylation, and PTP1B expression and activity. We also explore potential mechanisms through which adiponectin regulates SOCS-3-Ob-Rb association. Adiponectin inhibits leptin-stimulated JAK2 activation and Ob-Rb phosphorylation in HSCs, whereas both were increased in Ad-/- mice. Adiponectin stimulates PTP1B expression and activity in vitro, whereas PTP1B expression was lower in Ad-/-mice than in wild-type mice. Adiponectin also promotes SOCS-3-Ob-R association and blocks leptin-stimulated formation of extracellular TIMP-1 (tissue inhibitor of metalloproteinases-1)-MMP-1 (matrix metalloproteinase-1) complexes in vitro. These results suggest two novel mechanisms whereby adiponectin inhibits hepatic fibrosis: (i) by promoting binding of SOCS-3 to Ob-Rb, and (ii) by stimulating PTP1B expression and activity, thus inhibiting JAK2/STAT3 signalling at multiple points.

Topics: Adiponectin; Animals; Carbon Tetrachloride; Cells, Cultured; Cytoprotection; Gene Knockout Techniques; Hepatic Stellate Cells; Humans; Janus Kinase 2; Leptin; Liver Cirrhosis; Male; Matrix Metalloproteinase 1; Mice; Mice, Knockout; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Recombinant Proteins; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Tissue Inhibitor of Metalloproteinase-1

Protein-energy malnutrition is frequently observed in patients with liver cirrhosis and is associated with their poor prognosis. Tumor necrosis factor-alpha (TNF-alpha) is elevated in those patients and may contribute to the alterations of energy metabolism. Our aim was to characterize the aberrant energy metabolism in cirrhotic patients with regard to TNF-alpha.. Twenty-four patients (mean age 65 +/- 6 y) with viral liver cirrhosis who did not have hepatocellular carcinoma or acute infections were studied. Twelve healthy volunteers were recruited after matching for age, gender, and body mass index with the patients and served as controls (59 +/- 8 y). Serum levels of TNF-alpha, soluble 55-kDa TNF receptor (sTNF-R55), soluble 75-kDa TNF receptor (sTNF-R75), and leptin were determined by immunoassay. Substrate oxidation rates of carbohydrate and fat were estimated by indirect calorimetry after overnight bedrest and fasting.. In cirrhotic patients, serum levels of TNF-alpha, sTNF-R55, and sTNF-R75 were significantly higher than those in the controls and correlated with the increasing grade of disease severity as defined by Child-Pugh classification. Serum leptin concentration was not different between cirrhotics and controls but correlated with their body mass index. The decrease in substrate oxidation rate of carbohydrate and the increase in substrate oxidation rate of fat significantly correlated with serum TNF-alpha, sTNF-R55, and sTNF-R75 concentrations.. Tumor necrosis factor-alpha might be associated with the aberrant energy metabolism in patients with liver cirrhosis.

Topics: Aged; Body Mass Index; Case-Control Studies; Dietary Carbohydrates; Dietary Fats; Energy Metabolism; Female; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Oxidation-Reduction; Protein-Energy Malnutrition; Receptors, Tumor Necrosis Factor; Severity of Illness Index; Tumor Necrosis Factor-alpha

Chronic hepatitis B patients with diabetes and metabolic syndrome are at increased risk of cirrhosis and hepatocellular carcinoma, but the underlying mechanism is unclear. Our objective was to test whether dysregulation of adipokines contributes to liver injury. We also studied whether viral factors affected adipokines, insulin resistance, and hepatic steatosis.. A prospective cohort of 266 chronic hepatitis B patients undergoing liver biopsy was studied. Fasting blood was taken for the analysis of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), adiponectin, leptin, and resistin. Insulin resistance was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR). Factors associated with significant necroinflammation and cirrhosis were identified.. Histological activity index was correlated with serum TNF-alpha (R=0.40, P<0.0001) and IL-6 (R=0.32, P<0.0001) but not with adiponectin, leptin, or resistin. By multivariate analysis, TNF-alpha was associated with significant necroinflammation after adjusting for age and viral factors (odds ratio (OR) 1.041, 95% confidence interval (CI) 1.002-1.082, P=0.04). Serum adiponectin had positive correlation with hepatitis B virus DNA (R=0.17, P=0.007) and was decreased in patients with insulin resistance and hepatic steatosis. On the other hand, viral load, hepatitis B e-antigen status, and genotypes had no association with insulin resistance, hepatic steatosis, and the levels of TNF-alpha and IL-6. A total of 68 (25.6%) patients had cirrhosis. HOMA-IR, but not adipokine dysregulation, was independently associated with cirrhosis (OR 1.09, 95% CI 1.02-1.15, P=0.006).. TNF-alpha and/or IL-6 contribute to hepatic necroinflammation in chronic hepatitis B patients. Adiponectin protects against insulin resistance and hepatic steatosis but does not affect liver injury. Adipokines and viral factors contribute to liver injury independently.

Topics: Adipokines; Adiponectin; Adult; Biopsy; China; Fatty Liver; Female; Hepatitis B, Chronic; Humans; Insulin Resistance; Interleukin-6; Leptin; Liver Cirrhosis; Logistic Models; Male; Middle Aged; Prospective Studies; Resistin; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

No detailed data are available on hepatic clearance, postprandial release, and distribution profile of metabolically active adipokines in splanchnic blood compartments such as portal and hepatic veins. This would be a prerequisite for understanding the role of visceral adipose tissue-derived adipokines in metabolism. Adiponectin, resistin, leptin, and visfatin concentrations were measured by enzyme-linked immunosorbent assay in peripheral veins, arterial blood, hepatic veins, and portal veins in 50 patients with liver cirrhosis undergoing transjugular intrahepatic portosystemic shunt implantation, in 6 patients with normal liver function, and in fasted and fed rats. Adiponectin, leptin, resistin, and visfatin did not differ among blood compartments in normal-weight probands in the fasted state. Adiponectin and leptin levels were similar in patients with and without liver cirrhosis. Systemic visfatin levels were decreased and resistin levels were increased in liver cirrhosis. Visfatin secretion was higher from visceral than from peripheral subcutaneous adipose tissue in liver cirrhosis. There was no hepatic clearance of visfatin. Leptin secretion was higher from peripheral than from visceral adipose tissue. Leptin did not undergo hepatic clearance. Resistin and adiponectin did not differ between blood compartments in liver cirrhosis. Resistin concentrations increased upon feeding in rats, and there was an increase in the postprandial clearance of adiponectin by the liver. A postprandial increase of leptin concentrations was restricted to peripheral adipose tissue in rats. The results give insight into the dynamics of splanchnic adipokine concentrations and help critically interpret data derived from messenger RNA expression studies.

Topics: Adipokines; Adiponectin; Animals; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Hepatic Veins; Humans; Intra-Abdominal Fat; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Portal Vein; Postprandial Period; Rats; Rats, Sprague-Dawley; Resistin; Splanchnic Circulation; Statistics, Nonparametric

The pathogenesis of anorexia in cirrhotic patients is complex and the appetite-modulating hormone ghrelin could be involved. Acylated ghrelin is the biologically active form that modifies insulin sensitivity and body composition. The aim of the present study was to compare acylated and total ghrelin concentration in patients with liver cirrhosis and to investigate the possible relationship between ghrelin and clinical and nutritional parameters.. Sixty patients with viral liver cirrhosis who did not have hepatocellular carcinoma or acute infections were studied. Twenty healthy volunteers were recruited after matching for age, gender, and body mass index with the patients and served as controls. Fasting levels of total, acylated ghrelin, leptin, TNF-alpha and insulin were measured in all subjects, in addition, clinical and nutrition parameters were assessed.. In cirrhotic patients, plasma levels of both acylated and total ghrelin were significantly higher than those in the controls. The mean plasma acylated ghrelin levels were significantly higher in Child C cirrhosis compared to Child A and B. Ghrelin (total and acylated) were negatively correlated with leptin in cirrhotic patients confirming the fact that leptin acts as a physiological counterpart of ghrelin.. Nutritional and metabolic abnormalities in cirrhotic patients may be dependent on the changes in the ghrelin/leptin systems, mainly the acylated form of ghrelin.

Topics: Acylation; Female; Ghrelin; Humans; Leptin; Liver Cirrhosis; Male; Tumor Necrosis Factor-alpha

Nonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of the metabolic syndrome and covers a large spectrum of liver diseases ranging from benign steatosis to steatohepatitis, cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is currently believed to involve various hits including lipotoxicity, gut-derived signals, inflammatory attacks directed by proinflammatory cytokines, oxidative stress and others. All these factors finally lead to the development of necroinflammation and fibrosis in a substantial proportion of patients. There is increasing evidence that mediators released from the adipose tissue in obese subjects, such as adipocytokines and classical cytokines, are key players in NAFLD. The prototypic adipocytokines adiponectin and leptin are able to regulate many features of NAFLD such as accumulation of liver fat, insulin resistance, inflammatory processes and development of fibrosis. Therefore, this heterogenous and rapidly growing family of mediators elegantly explains many aspects of NAFLD as demonstrated by numerous experimental and clinical studies.

Topics: Adipokines; Adiponectin; Animals; Cytokines; Fatty Liver; Humans; Inflammation; Leptin; Liver Cirrhosis; Obesity; Oxidative Stress

This study was conducted to investigate the effect of tetramethylpyrazine (TMP) on CCl(4)-induced fibrosis in rats and the possible roles of leptin, TGF-beta1, Smad3, and Smad7 in this process. Liver fibrosis in rats was induced by the subcutaneous injection of 60% CCl(4) (0.3 mL /100 g body weight, biweekly ) for 12 weeks. Rats in TMP prevention and treatment groups were given TMP (10 mg /100 g body weight, daily) by gavage from days 1 and 31 after the start of CCl(4) injection, respectively. The mRNA expression of leptin, OB-Rb, TGF-beta1, and TGF-beta RII in the liver were detected by RT-PCR, whereas Smad3 and Smad7 protein were determined by Western blot. The results showed that hepatic cirrhosis was obviously alleviated in both TMP prevention and treatment groups. The mRNA expression of leptin, OB-Rb, TGF-beta1 and -beta RII, and Smad3 protein were higher in the cirrhotic models. In TMP prevention and treatment groups, these markers of expression were higher, compared with that of the normal control, but were lower when compared with that of the cirrhotic model group. Smad7 protein expression was lower in the cirrhotic model group than in the normal control. Smad7 expression in TMP prevention and treatment groups was higher, compared with that in the cirrhotic model group. Liver collagen in the TMP prevention group was the lowest among all CCl(4) injection groups. In conclusion, TMP can prevent and alleviate the development of liver fibrosis in rats. The possible mechanism could involve the downregulation of leptin, Ob-Rb, TGF-beta1, TGF-beta RII, and Samd3, and upregulation of Smad7.

Topics: Animals; Blotting, Western; Carbon Tetrachloride; Down-Regulation; Fibrinolytic Agents; Histocytochemistry; Leptin; Liver Cirrhosis; Male; Pyrazines; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Smad3 Protein; Smad7 Protein; Transforming Growth Factor beta1

There is no animal model that displays the features of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance (IR) and fibrosing steatohepatitis. This study aimed to develop a novel IR-associated rat model of NASH.. Male Sprague-Dawley rats were fed with the high-fat diet (HFD) supplemented with 0.25% propylthiouracil for 2, 4, 6, 8 and 12 weeks. The IR-associated metabolic parameters, histological assessment and the expression of key insulin signaling molecules were determined. The circulating and tissue pro-inflammatory factors and adipocytokines were examined.. In the HFD-fed rats, the systemic and multiple-organ IR was developed after 4 weeks, whereas the histological changes characterized by steatohepatitis, inflammatory response in the visceral adipose tissue and proliferative pancreatic islet β-cells appeared after 6 weeks, concomitant with altered expression of key insulin signaling molecules. In addition, the elevated levels of serum tumor necrosis factor α (TNF-α), soluble TNF receptor2, interleukin (IL)-6, CC-chemokine ligand (CCL)2 and resistin were parallel with the severity of hepatic inflammation, while the levels of serum adiponectin, leptin and TNF-α, but not resistin, were correlated with IR.. We have developed a systemic IR-associated NASH model of rats, with impaired insulin signaling, systemic inflammation and appropriate pathology characterized by human NASH, and provided a realistic experimental model for elucidating the association between IR and the pathogenesis of NASH.

Topics: Adiponectin; Animals; Chemokines; Disease Models, Animal; Disease Progression; Fatty Liver; Gene Expression Regulation; Hepatitis; Insulin Resistance; Leptin; Liver Cirrhosis; Male; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Resistin; RNA; Severity of Illness Index

Adiponectin is an adipocytokine that was recently shown to be anti-fibrogenic in hepatic fibrosis. Leptin, on the other hand, promotes hepatic fibrosis. The purpose of the present study was to elucidate a mechanism (or mechanisms) whereby adiponectin dampens leptin signaling in activated hepatic stellate cells (HSCs), and prevents excess extracellular matrix production. Activated HSCs, between passages 2 and 5, were cultured and exposed to recombinant human adiponectin and recombinant leptin. Immunoblot analysis for SOCS-3, TIMP-1, and the phosphorylated species of Stat3 and adenosine monophosphate-activated protein kinase (AMPK) were conducted. We also examined MMP-1 activity by immunosorbant fluorimetric analysis. In HSCs, adiponectin-induced phosphorylation of AMPK, and subsequently suppressed leptin-mediated Stat3 phosphorylation and SOCS-3 induction. Adiponectin also blocked leptin-stimulated secretion of TIMP-1, and significantly increased MMP-1 activity, in vitro. To extend this study, we treated adiponectin knockout mice (Ad-/-) daily with 5 mg/kg recombinant leptin and/or carbon tetrachloride (2 ml/kg) for 6 weeks. Post-necropsy analysis was performed to examine for inflammation, and histological changes in the Ad-/- and wild-type mice. There was no significant difference in inflammation, or aminotransferases, between mice receiving carbon tetrachloride and leptin versus carbon tetrachloride alone. As anticipated, the combination of leptin and CCl(4) enhanced hepatic fibrosis in both wild-type and Ad-/- mice, as estimated by amount of collagen in injured livers, but wild-type mice had significantly higher levels of SOCS-3 and significantly lower levels of TIMP-1 mRNA and protein than did adiponectin KO mice exposed to both CCl(4) and leptin. We therefore conclude that the protective effects of adiponectin against liver fibrosis require AMPK activation, and may occur through inhibition of the Jak-Stat signal transduction pathway.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Blotting, Western; Carbon Tetrachloride; Cells, Cultured; Female; Hepatic Stellate Cells; Humans; Leptin; Liver Cirrhosis; Male; Matrix Metalloproteinase 1; Mice; Mice, Knockout; Phosphorylation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling Proteins; Tissue Inhibitor of Metalloproteinase-1; Transfection

Mechanisms linking obesity and unfavourable outcomes in patients with viral hepatitis C (HCV) cirrhosis are not well understood. Obesity is associated with insulin resistance, increased leptin, and decreased adiponectin serum levels.. We assessed the predictive value of those factors for the occurrence of hepatocellular carcinoma (HCC) and liver-related death or transplantation in a cohort of 248 patients (mean age 58 (12 years, BMI 25.4 ± 4.4 kg/m(2)) with compensated HCV cirrhosis and persistent infection prospectively followed and screened for HCC.. The mean baseline serum levels of adiponectin and leptin were 16.8 ± 15 mg/L and 16.8 ± 19 ng/ml, respectively. The mean homeostasis model assessment of insulin resistance (HOMA) index was 3.8 ± 3; median 2.9. After a median follow-up of 72 months, 61 patients developed HCC, 58 died of liver causes, and 17 were transplanted. The incidences (Kaplan Meier) of HCC were 7%, 18%, and 27% at 5 years (p=0.017) and of liver-related death or transplantation 15%, 15% and 29% (p=0.002) according to the lowest, middle and highest tertile of HOMA, respectively. In multivariate analysis, the HOMA index was associated with HCC occurrence (HR=1.10, [1.01-1.21] p=0.026) and was a strong predictor of liver-related death or transplantation (HR=1.13, [1.07-1.21] p<0.0001). Serum levels of adiponectin and leptin were not associated with the outcome.. In patients with compensated HCV cirrhosis, insulin resistance but not serum levels of adiponectin and leptin predicted the occurrence of HCC and of liver-related death or transplantation.

Topics: Adiponectin; Adult; Aged; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Hepatitis C; Humans; Insulin Resistance; Leptin; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Risk Factors

The study included 95 children with chronic hepatic disorders of different etiology. All of them underwent hepatic puncture biopsy for morphological studies and calculation of histological sclerosis index based on the Knoddel scale. Commercial enzyme immunoassay kits were used to measure hyaluronic acid (HA), type IV collagen (CIV), matrix metalloproteinase-1 (MMP-2), transforming growth factor-beta 1 (TGF), and leptin levels as non-invasive markers of fibrosis. It was shown that concentrations of TGF and MMP-2 at early stages of hepatic fibrosis, HA and CIV at its later stages are of diagnostic value.

Topics: Adolescent; Biomarkers; Child; Child, Preschool; Collagen Type IV; Humans; Hyaluronic Acid; Infant; Leptin; Liver Cirrhosis; Matrix Metalloproteinase 2; Sensitivity and Specificity; Transforming Growth Factor beta1

Leptin signaling is involved in T-cell polarization and is required for profibrotic function of hepatic stellate cells (HSCs). Leptin-deficient ob/ob mice do not develop liver fibrosis despite the presence of severe long-standing steatohepatitis. Here, we blocked leptin signaling with our recently generated mouse leptin antagonist (MLA), and examined the effects on chronic liver fibrosis in vivo using the chronic thioacetamide (TAA) fibrosis model, and in vitro using freshly-isolated primary HSCs. In the chronic TAA fibrosis model, leptin administration was associated with significantly enhanced liver disease and a 100% 5-week to 8-week mortality rate, while administration or coadministration of MLA markedly improved survival, attenuated liver fibrosis, and reduced interferon gamma (IFN-gamma) levels. No significant changes in weight, serum cholesterol, or triglycerides were noted. In vitro administration of rat leptin antagonist (RLA), either alone or with leptin, to rat primary HSCs reduced leptin-stimulated effects such as increased expression of alpha-smooth muscle actin (alpha-SMA), and activation of alpha1 procollagen promoter.. Inhibition of leptin-enhanced hepatic fibrosis may hold promise as a future antifibrotic therapeutic modality.

Topics: Animals; Female; Hepatic Stellate Cells; Hormone Antagonists; Leptin; Liver; Liver Cirrhosis; Mice; Models, Animal; Platelet-Derived Growth Factor; Rats; Signal Transduction; Thioacetamide

Leptin has profibrogenic effects in liver, although the mechanisms of this process are unclear. We sought to elucidate the direct and indirect effects of leptin on hepatic stellate cells (HSCs).. HSCs from Sprague-Dawley rats were exposed to leptin and expression of collagen-I, tissue inhibitor of matrix metalloproteinases-1 (TIMP1), transforming growth factor beta1 (TGF-beta1), and connective tissue growth factor (CTGF/CCN2) was assessed. The effects of medium from Kupffer cells (KCs) and sinusoidal endothelial cells (SECs) following leptin were evaluated in HSCs; alpha-smooth muscle actin (alphaSMA) production and KC signaling were analyzed.. HSCs were not activated by incubation with leptin. However, HSCs cultured with medium taken from KCs that were incubated with leptin had increased expression of collagen I, TIMP1, TGF-beta1, and CTGF/CCN2, as well as alphaSMA protein levels and proliferation. These effects were leptin receptor dependent because conditioned medium from KCs isolated from leptin receptor-deficient Zucker (fa/fa) rats did not activate HSCs. In KCs incubated with leptin, messenger RNA and protein expression of TGF-beta1 and CTGF/CCN2 increased. Leptin potentiated signal transducer and activator of transcription 3, AKT, and extracellular signal-related kinase 1/2 phosphorylation in KCs and increased AP-1 and nuclear factor-kappaB DNA binding. Finally, addition of anti-TGF-beta to KC-conditioned medium inhibited HSC expression of collagen I, TIMP1, and CTGF/CCN2, whereas signal transducer and activator of transcription 3 inhibitor attenuated TGF-beta1 production by KC.. Leptin mediates HSC activation and liver fibrosis through indirect effects on KC; these effects are partly mediated by TGF-beta1.

Topics: Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Hepatic Stellate Cells; Hydrogen Peroxide; Immunoblotting; Immunohistochemistry; Kupffer Cells; Leptin; Liver Cirrhosis; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity; Transforming Growth Factor beta1; Up-Regulation

The aim of this study was to determine whether serum levels of adipokines, including the ratio of serum adiponectin to leptin (A/L) levels could predict the severity of liver injury in patients with non-alcoholic fatty liver disease (NAFLD).. Fifty-seven patients with biopsy-proven non-alcoholic steatohepatitis (NASH) (mean age 51+/-12, sex ratio 1), 17 with simple steatosis (mean age 47+/-12, sex ratio 1.4) and 10 controls without steatosis (mean age 51+/-11, sex ratio 4) were investigated. In all subjects, serum concentrations of triglycerides, ultrasensitive C reactive protein, leptin, adiponectin, soluble tumour necrosis factor receptor 1, interleukin (IL)-6 and Homeostasis Model Assessment Method (HOMA) were measured. Hepatic expression of adiponectin and its two receptors was assessed by quantitative reverse transcriptase polymerase chain reaction.. Body mass index (BMI) and HOMA were correlated positively with leptin levels (r=0.44 and 0.28 respectively) and negatively with the A/L ratio (r=0.51 and 0.41 respectively). Independent parameters associated with NASH vs steatosis were HOMA>3 [odds ratio (OR)=6.9] and A/L ratio <1.4 10(3) (OR=5.2). The combination of HOMA with A/L ratio showed an area under the receiver operating characteristic curve of 0.82 for distinguishing between NASH and steatosis. Extensive portal fibrosis was present in 17 (23%) patients with NAFLD. Three independent parameters were associated with fibrosis: age (OR=1.1), BMI (OR=1.3) and high IL-6 levels (OR=1.6). The hepatic expression of adiponectin receptor 2 was significantly higher in patients with NASH compared with controls and was related with necroinflammatory injury.. This study shows that in patients with NAFLD, the combination of HOMA with A/L ratio may be a useful non-invasive approach to appreciate the severity of liver damage.

Topics: Adiponectin; Adult; Aged; Fatty Liver; Female; Humans; Insulin Resistance; Interleukin-6; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged; Receptors, Adiponectin; RNA, Messenger

In the nontransplant setting diabetes mellitus is a risk factor for disease progression in patients with chronic hepatitis C virus (HCV) infection. The impact of early insulin resistance on the development of advanced fibrosis, even in the absence of clinically apparent diabetes mellitus, is not known. Our aim was to determine whether the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) can be used to identify insulin-resistant patients at risk for rapid fibrosis progression. Cohort study including patients transplanted for chronic HCV between January 1, 1995 and January 1, 2005. One hundred sixty patients were included; 25 patients (16%) were treated for diabetes mellitus and 36 patients (23%) were prediabetic, defined as HOMA-IR >2.5. Multivariate Cox regression analysis showed that insulin resistance (hazard ratio (HR) 2.07; confidence interval (CI) 1.10-3.91, p = 0.024), donor age (HR 1.33;CI 1.08-1.63, p = 0.007) and aspartate aminotransferase (HR 1.03;CI 1.01-1.05, p < 0.001) were significantly associated with a higher probability of developing advanced fibrosis, i.e. Knodell fibrosis stage 3 or 4, whereas steatosis (HR 0.94;CI 0.46-1.92, p = 0.87) and acute cellular rejection (HR 1.72;CI 0.88-3.36, p = 0.111) were not. In conclusion, posttransplant insulin resistance is strongly associated with more severe recurrence of HCV infection. HOMA-IR is an important tool for the identification of insulin resistance among patients at risk for rapid fibrosis progression after liver transplantation for HCV.

Topics: Adipokines; Adult; Cohort Studies; Diabetes Complications; Disease Progression; Female; Hepatitis C, Chronic; Humans; Insulin Resistance; Kaplan-Meier Estimate; Leptin; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Prediabetic State; Regression Analysis; Risk

Topics: Animals; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Gene Expression Regulation, Enzymologic; Hepatic Stellate Cells; Leptin; Liver Cirrhosis; Matrix Metalloproteinase 2; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

This investigation was designed to assess the effects of oral administration of melatonin (10 mg) and tryptophan (Trp) (500 mg) on fasting and postprandial plasma levels of melatonin, gastrin, ghrelin, leptin and insulin in 10 healthy controls and in age-matched patients with liver cirrhosis (LC) and portal hypertension. Fasting plasma melatonin levels in LC patients were about five times higher (102 +/- 15 pg/mL) than in healthy controls (22 +/- 3 pg/mL). These levels significantly increased postprandially in LC patients, but significantly less so in controls. Treatment with melatonin or L-Trp resulted in a further significant rise in plasma melatonin, both under fasting and postprandial conditions, particularly in LC patients. Moreover, plasma gastrin, ghrelin, leptin and insulin levels under fasting and postprandial conditions were significantly higher in LC subjects than in healthy controls and they further rose significantly after oral application of melatonin or Trp. This study shows that: (a) patients with LC and portal hypertension exhibit significantly higher fasting and postprandial plasma melatonin levels than healthy subjects; (b) plasma ghrelin, both in LC and healthy controls reach the highest values under fasting conditions, but decline postprandially, especially after oral application of melatonin or Trp; and (c) plasma melatonin, gastrin, ghrelin and insulin levels are altered significantly in LC patients with portal hypertension compared with that in healthy controls possibly due to their portal systemic shunting and decreased liver degradation.

Topics: Administration, Oral; Basal Metabolism; Case-Control Studies; Data Interpretation, Statistical; Gastrins; Ghrelin; Humans; Hypertension, Portal; Insulin; Leptin; Liver Cirrhosis; Male; Melatonin; Peptide Hormones; Postprandial Period; Tryptophan

Hepatic steatosis and fibrosis are common histological findings in patients with chronic hepatitis C virus (HCV) infection. In this study we sought to determine whether serum levels of three adipokines (leptin, adiponectin and resistin) show any biochemical correlation with hepatic steatosis and fibrosis in patients with chronic HCV infection.. We examined a total of 51 patients with chronic HCV infection (22 males and 29 females, mean BMI: 27.4+/-5kg/m(2)) and 24 healthy control subjects (10 males and 14 females, mean BMI: 23.2+/-3kg/m(2)). Liver steatosis and fibrosis were scored on biopsies. Serum levels of leptin, adiponectin and resistin were determined by ELISA.. HCV genotypes were 1b in 41 patients (80.4%), 3a in three patients (5.9%), 2a in two patients (3.9%), 1a in two patients (3.9%), 1c in one patient (2%), and 2b in one patient (2%). Serum levels of leptin, resistin, and the leptin-to-adiponectin ratio were significantly higher in patients with chronic HCV infection than in controls. Steatosis and fibrosis were detected in 33.3% and 70.5% of chronic HCV patients, respectively. No significant association with serum adipokine levels and degree of steatosis was evident. Low serum levels of resistin were associated with the presence of fibrosis independently of potential confounders.. Patients with chronic HCV infection display elevated levels of adipokines in their sera. Reduced concentrations of resistin may be a biochemical marker of fibrosis in this patient group.

Topics: Adiponectin; Adult; Body Mass Index; Fatty Liver; Female; Hepatitis C, Chronic; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Resistin

Although leptin induces fibrotic activity in hepatic stellate cells (HSCs), the mechanisms are not entirely understood. To investigate the potential role of reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH) and reactive oxygen species (ROS) in leptin signaling in HSCs, we analyzed leptin-induced intracellular signaling pathways in primary wild-type (WT), p47(phox(-/-) ), and signal transducer and activator of transcription protein 3 (STAT3)-deleted HSCs. Leptin-stimulated ROS production was attenuated in human and mouse HSCs by the NADPH oxidase inhibitor diphenylene-iodonium (DPI) and in HSCs lacking the NADPH component p47(phox). Leptin-induced phosphorylation of extracellular signal-regulated kinase (ERK) and AKT, but not of STAT3, was blocked by NADPH oxidase inhibition. Moreover, leptin-induced ROS production was inhibited by the Janus kinase (JAK) inhibitor, AG490, but normal ROS production was observed in STAT3-deleted HSCs. Pharmacologic or genetic inhibition of NADPH in HSCs not only resulted in a reduction of leptin-mediated HSC proliferation but also reduced the leptin-mediated up-regulation of the fibrogenic markers collagen alpha1(I) and alpha-smooth muscle actin and of the inflammatory mediators monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein 1 (MIP-1), and macrophage inflammatory protein 2 (MIP-2). In vivo, leptin enhanced chemokine expression induced by chemokine (C-C motif) ligand 4 (CCl(4)) in WT mice, but a blunted response was observed in p47(phox-/-) mice. In conclusion, NADPH oxidase is a crucial mediator of proliferative, fibrogenic, and inflammatory actions of leptin. Leptin-induced NADPH oxidase acts downstream of JAK activation but is independent of STAT3. Our results, in conjunction with previous studies on angiotensin II and platelet-derived growth factor (PDGF), place NADPH in the center of the fibrogenic signaling response in HSCs and demonstrate its potential role as a pharmacological target for antifibrotic therapies.

Topics: Animals; Cell Proliferation; Cells, Cultured; Chemokines; Disease Models, Animal; Hepatic Stellate Cells; Janus Kinases; Leptin; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidases; Reactive Oxygen Species; Signal Transduction; STAT3 Transcription Factor

Both steatosis and insulin resistance have been linked to accelerated fibrosis in chronic hepatitis C. Connective tissue growth factor (CTGF) plays a major role in extracellular matrix production in fibrotic disorders including cirrhosis, and its expression is stimulated in vitro by insulin and glucose. We hypothesized that CTGF may link steatosis, insulin resistance and fibrosis.. We included 153 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study and for whom a liver biopsy and plasma samples were available. CTGF expression was assessed quantitatively by immunohistochemistry. In 94 patients (57 with genotypes non-3), plasma levels of glucose, insulin and leptin were also measured. CTGF synthesis was investigated by immunoblotting on LX-2 stellate cells.. Connective tissue growth factor expression was higher in patients with steatosis (P=0.039) and in patients with fibrosis (P=0.008) than those without these features. CTGF levels were neither associated with insulinaemia or with glycaemia, nor with inflammation. By multiple regression analysis, CTGF levels were independently associated with steatosis, a past history of alcohol abuse, plasma leptin and HCV RNA levels; when only patients with genotypes non-3 were considered, CTGF levels were independently associated with a past history of alcohol abuse, plasma leptin levels and steatosis. Leptin stimulated CTGF synthesis in LX-2 cells.. In patients with chronic hepatitis C and steatosis, CTGF may promote fibrosis independently of inflammation. CTGF may link steatosis and fibrosis via increased leptin levels.

Topics: Adult; Blood Glucose; Connective Tissue Growth Factor; Fatty Liver; Female; Hepatitis C, Chronic; Humans; Immediate-Early Proteins; Immunoblotting; Immunohistochemistry; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Liver Cirrhosis; Male; Middle Aged; Switzerland

Histopathology is essential in the diagnostic workup of most liver diseases. However, biopsy sampling might carry risks, is subject to sampling error, and does not provide dynamic tissue imaging. Therefore a newly developed miniaturised confocal probe was evaluated for in vivo microscopic imaging in rodent models of human liver diseases.. The handheld laparoscopy probe used a 488nm single line laser for fluorophore excitation. Optical slice thickness was 7 microm, lateral resolution 0.7 microm. Imaging depth was 0-250 microm below the tissue surface. Imaging using different fluorescent staining protocols was performed in healthy mice, IFN-gamma- and IL-12-induced hepatitis, after bile duct ligation, and in ob/ob mice.. Confocal imaging permitted microscopic imaging of the liver in vivo at high resolution. Landmarks of liver diseases such as inflammatory infiltration, steatosis, bile duct proliferation, pericellular fibrosis and perfusion anomalies could be characterised, localised and differentiated in vivo.. In vivo confocal microscopy with this newly developed probe allows real-time subsurface imaging and characterisation of normal and pathologic liver tissue at high resolution. Since this technology is suited for laparoscopy in humans, it has the potential to impact on the diagnostic workup of liver diseases and to permit dynamic monitoring of (patho-)physiologic events in vivo.

Topics: Acriflavine; Animals; Chemical and Drug Induced Liver Injury; Common Bile Duct; Cytokines; Dextrans; Disease Models, Animal; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Laparoscopy; Leptin; Ligation; Liver; Liver Cirrhosis; Liver Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal

The biological basis of variability in histological progression of nonalcoholic fatty liver disease (NAFLD) is unknown. Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone and has been shown to influence sensitivity to oxidative stress, insulin sensitivity, and expression of peroxisome proliferator-activated receptor alpha and procollagen messenger RNA. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of DHEA. Serum samples were obtained prospectively at the time of liver biopsy in 439 patients with NAFLD (78 in an initial and 361 in validation cohorts) and in controls with cholestatic liver disease (n = 44). NAFLD was characterized as mild [simple steatosis or nonalcoholic steatohepatitis (NASH) with fibrosis stage 0-2] or advanced (NASH with fibrosis stage 3-4). Serum levels of sulfated DHEA (DHEA-S) were measured by enzyme-linked immunosorbent assay. Patients with advanced NAFLD had lower plasma levels of DHEA-S than patients with mild NAFLD in both the initial (0.25 +/- 0.07 versus 1.1 +/- 0.09 microg/mL, P < 0.001) and validation cohorts (0.47 +/- 0.06 versus 0.99 +/- 0.04 microg/mL, P < 0.001). A "dose effect" of decreasing DHEA-S and incremental fibrosis stage was observed with a mean DHEA-S of 1.03 +/- 0.05, 0.96 +/- 0.07, 0.83 +/- 0.11, 0.66 +/- 0.11, and 0.35 +/- 0.06 microg/mL for fibrosis stages 0, 1, 2, 3, and 4, respectively. All patients in both cohorts in the advanced NAFLD group had low DHEA-S levels, with the majority in the hypoadrenal range. The association between DHEA-S and severity of NAFLD persisted after adjusting for age. A relationship between disease/fibrosis severity and DHEA-S levels was not seen in patients with cholestatic liver diseases.. More advanced NAFLD, as indicated by the presence of NASH with advanced fibrosis stage, is strongly associated with low circulating DHEA-S. These data provide novel evidence for relative DHEA-S deficiency in patients with histologically advanced NASH.

Topics: Adiponectin; Adult; Biomarkers; Biopsy; Blood Glucose; C-Reactive Protein; Cohort Studies; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Fatty Liver; Female; Humans; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged; Reference Values; Resistin

To investigate the mechanism underlying the protective effects of a traditional Chinese medicinal formula, Baoganning, against liver fibrosis.. Male Wistar rats were subjected to injection of carbon tetrachloride- peanut oil mixture and given daily 5% alcoholic beverage, and 2 days after the injection, Baoganning was administered intragastrically at two different doses for 6 weeks. Radioimmunoassay was used to detect serum leptin level, and immunohistochemistry employed to examine the effect of Baoganning on expressions of leptin and its receptor in the liver tissue of the rats.. Compared with the normal control group, the rats in the liver fibrosis model group and Baoganning-treated groups showed significantly increased serum leptin levels (P<0.01), and the serum leptin level was significantly lower in Baoganning group than in the liver fibrosis model group (P<0.01). Baoganning significantly reduced the hepatic expression of leptin and OB-Rb in rats with liver fibrosis in comparison with their expression in the model group (P<0.01).. Baoganning can effectively ameliorate liver fibrosis in rats possibly through reducing serum leptin level and inhibiting hepatic leptin and its receptor expressions.

Topics: Animals; Carbon Tetrachloride; Drugs, Chinese Herbal; Leptin; Liver; Liver Cirrhosis; Male; Phytotherapy; Radioimmunoassay; Random Allocation; Rats; Rats, Wistar; Receptors, Leptin

Collagen accumulation in liver fibrosis is due in part to decreased expression of matrix metalloproteinase (MMP)-1 relative to TIMP-1. LX-2 hepatic stellate cells produce increased amounts of collagen and tissue inhibitor of metalloproteinase (TIMP)-1 in response to leptin. The effect of leptin on MMP-1 production has not been reported.. LX-2 cells were treated with leptin with or without inhibitors. We determined: phosphorylation of Janus kinase (JAK) 1 and -2, signal transducer and activator of transcription (STAT)3 and -5, extracellular signal-regulated kinase (ERK)1/2 and p38 by Western blot; H2O2 concentration by a colorimetric method; MMP-1 mRNA levels and stability by Northern blot; MMP-1 promoter activity as well as pro-MMP-1 by ELISA; and active MMP-1 by fluorescence.. LX-2 cells constitutively expressed the MMP-1 gene and leptin repressed the basal level of MMP-1 mRNA and its promoter activity. The repression was mediated by JAK/STAT pathway in synergism with JAK-mediated H2O2-dependent ERK1/2 and p38 pathways. ERK1/2 inhibited MMP-1 promoter activity, whereas p38 decreased the message stability, contributing to mRNA down-regulation. Inhibition of MMP-1 gene diminished secreted pro-MMP-1 and active MMP-1.. Leptin represses MMP-1 gene expression via the synergistic actions of the JAK/STAT pathway and JAK-mediated H2O2-dependent ERK1/2 and p38 pathways.

Topics: Base Sequence; Catalase; Cell Line; Down-Regulation; Enzyme Inhibitors; Hepatocytes; Humans; Hydrogen Peroxide; Imidazoles; Janus Kinases; Leptin; Liver Cirrhosis; MAP Kinase Signaling System; Matrix Metalloproteinase 1; Models, Biological; Oligodeoxyribonucleotides, Antisense; Pyridines; RNA, Messenger; STAT3 Transcription Factor; STAT5 Transcription Factor; Tyrphostins

Liver cirrhosis is associated with reduced energy intake and increased resting energy expenditure.. We aimed to investigate the possible role of glucose, insulin, leptin, and ghrelin in the pathogenesis of these alterations.. Nutritional status, energy intake, resting energy expenditure, and fasting glucose, insulin, and leptin were assessed in 31 patients with cirrhosis. Postprandial glucose, insulin, C-peptide, leptin, and ghrelin responses were studied in a subgroup of patients after a standard meal. Ten healthy subjects served as controls.. Patients with cirrhosis had a lower energy intake (P < 0.05), higher resting energy expenditure (P < 0.05), higher fasting leptin (P < 0.05), and higher insulin resistance (P < 0.001) than did the healthy control subjects. In the patients with cirrhosis, fasting leptin was negatively correlated with resting energy expenditure (r = -0.38, P < 0.05) but not with energy intake. In control subjects, leptin was negatively correlated with energy intake (r = -0.72, P < 0.05) but not with resting energy expenditure. The patients with cirrhosis had higher postprandial glucose (P < 0.001) and lower ghrelin (P < 0.05) concentrations at 4 h postprandially than did the control subjects. The increase in ghrelin from its minimal postmeal value to 4 h postmeal was negatively correlated (r = -0.66, P = 0.014) with weight loss in the patients with cirrhosis. Energy intake was negatively correlated (r = -0.42, P < 0.01) with the postprandial increase in glucose.. In cirrhosis, altered postprandial glucose and ghrelin are associated with reduced energy intake and weight loss, respectively, and the effects of leptin on energy intake and expenditure seem to be altered. Insulin resistance might be involved in these altered postprandial responses.

Topics: Basal Metabolism; Blood Glucose; Body Mass Index; Body Weight; Calorimetry, Indirect; Eating; Energy Intake; Female; Ghrelin; Humans; Insulin; Leptin; Liver Cirrhosis; Male; Middle Aged; Nutritional Status; Peptide Hormones; Postprandial Period

Steatosis is common in hepatitis C virus (HCV)-infected patients and likely accelerates fibrosis progression. Leptin, the peptide product of the obesity gene (ob), has been implicated in hepatic fibrogenesis; circulating levels of leptin correlate with body fat mass. The objective of the present study was to determine the clinical and histological correlates of serum leptin in HCV-infected patients, and to determine its utility in predicting liver histological lesions.. In 62 patients with chronic HCV, serum leptin was measured using a commercially available immunoassay. Associations between leptin, metabolic parameters, and severe hepatic fibrosis (stages 2 to 4) and steatosis (30% or greater) were determined. The utility of leptin in predicting liver histology was determined using receiver operating characteristic (ROC) curves.. The median body mass index (BMI) was 23.2 kg/m2 (range 17.7 kg/m2 to 35.6 kg/m2); 16% of patients (n=10) had HCV genotype 3. Severe fibrosis and steatosis were present in 23% and 13% of patients, respectively. Leptin was strongly correlated with the BMI, and its levels were higher in women. BMI-corrected leptin levels were not independently associated with severe fibrosis but were significantly associated with steatosis (OR of 1.07; 95% CI 1.01 to 1.04). On it own, leptin was poorly predictive of severe steatosis (area under the ROC curve was 0.64; 95% CI 0.42 to 0.87). However, its accuracy improved with the addition of HCV genotype (area under the ROC curve was 0.86; 95% CI 0.72 to 1.00; P=0.07).. As observed in the non-HCV setting, serum leptin correlates with BMI; higher leptin levels are found in women than men with chronic HCV. Serum leptin is a poor predictor of HCV-related fibrosis but may play a role in predicting steatosis when combined with HCV genotype.

Topics: Adult; Aged; Body Mass Index; Cohort Studies; Cross-Sectional Studies; Fatty Liver; Female; Hepatitis C, Chronic; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Predictive Value of Tests; Sex Factors

Alteration of the leptin system appears to play a role in the inflammatory-metabolic response in catabolic diseases such as chronic liver diseases.. To investigate the association between leptin components, inflammatory markers and hepatic energy and substrate metabolism.. We investigated in vivo hepatic substrate and leptin metabolism in 40 patients employing a combination of arterial and hepatic vein catheterization techniques and hepatic blood flow measurements. In addition to metabolic, inflammatory and neuroendocrine parameters, circulating levels of free leptin, bound leptin and soluble leptin receptor were determined.. Compared with controls, bound leptin and soluble leptin receptor levels were significantly elevated in cirrhosis, while free leptin did not increase. In cirrhosis bound leptin was correlated with soluble leptin receptor (r = 0.70, P < 0.001). Free leptin was positively correlated with metabolic parameters such as energy storage (body fat mass; r = 0.36, P < 0.05), insulin and insulin resistance (r = 0.48; r = 0.46, P < 0.01) as well as with hepatic glucose and energy release (r = 0.35 and r = 0.40, P < 0.05). In contrast, bound leptin and soluble leptin receptor were linked to proinflammatory cytokines and sympathetic activity (r = 0.61 and r = 0.56, P < 0.01).. The components of the leptin system (free leptin, bound leptin and soluble leptin receptor) have distinct roles in metabolic and inflammatory processes in patients with liver cirrhosis. The better understanding of this metabolic and inflammatory tissue-repair response may lead to innovative new therapeutic strategies in liver disease as well as in various other catabolic diseases.

Topics: Adult; Case-Control Studies; Cytokines; Female; Hepatitis; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Receptors, Leptin

Obesity and insulin resistance are the key factors for progression of hepatic fibrosis in various chronic liver diseases including non-alcoholic steatohepatitis (NASH). Recently it has been shown that leptin plays a pivotal role in development of hepatic fibrosis. Leptin promotes hepatic fibrogenesis through upregulation of transforming growth factor-beta in Kupffer cells and sinusoidal endothelial cells. Further, leptin facilitates proliferation and prevents apoptosis of hepatic stellate cells. There is a paradox, however, in that ob/ob mice and Zucker rats, which are the obese and diabetic strains, had minimal profibrogenic responses in the liver, most likely because they lack leptin and its receptors. To establish a more clinically relevant model to study the mechanism of fibrogenesis under steatohepatitis, fatty changes and profibrogenic responses in the liver caused by methionine-choline deficiency (MCD) were investigated in the KK-A(y) mouse, which is an obese and diabetic strain. KK-A(y) mice developed more severe hepatic steatosis, inflammation and fibrosis induced by an MCD diet as compared to C57Bl/6 controls. Importantly, KK-A(y) mice lack physiological upregulation of adiponectin levels, suggesting that adiponectin plays a pivotal role not only in regulation of insulin sensitivity but also in modulation of inflammatory and profibrogenic responses in dietary steatohepatitis. Collectively, these findings support the hypothesis that the balance of adipocytokine expression is a key regulator for the progression of hepatic fibrosis in the setting of steatohepatitis.

Topics: Adiponectin; Animals; Choline Deficiency; Disease Models, Animal; Disease Progression; Fatty Liver; Kupffer Cells; Leptin; Liver; Liver Cirrhosis; Methionine; Mice; Mice, Inbred C57BL; Oxidative Stress; Transforming Growth Factor beta1; Up-Regulation

The role of tumor necrosis factor alpha, interleukin 6, leptin, and adiponectin in the pathogenesis of hepatitis C virus (HCV)-associated insulin resistance (IR) remains controversial. We tested the hypothesis that these adipocytokines contribute to chronic HCV-associated IR and liver injury by first comparing their serum levels and homeostasis model assessment of insulin resistance (HOMA-IR) in 154 untreated, non-diabetic, HCV-infected male subjects with fibrosis stage 0-2, to that in 75 healthy volunteers matched for age, body mass index (BMI), and waist-hip ratio (WHR). We next examined whether the adipocytokine levels were associated with the extent of hepatic steatosis, portal/periportal inflammation and fibrosis in our total cohort of 240 HCV-infected male subjects. Significantly higher levels of HOMA-IR (2.12 versus 1.63, P = 0.01), TNFalpha (1.28 versus 0.60 pg/ml, P < 0.001) and IL6 (2.42 versus 1.15 pg/ml, P = 0.001) were noted in the HCV cohort compared with healthy controls respectively, but there were no significant differences in leptin and adiponectin concentrations. By multiple linear regression, independent predictors of HOMA-IR included the body mass index, and the serum levels of leptin (positive correlation) and adiponectin (negative correlation), but not that of TNFalpha and IL6. Only TNFalpha levels were correlated with the extent of histological injury (portal/periportal inflammation, P = 0.02).. Whereas leptin and adiponectin contribute to IR, none of the adipocytokines accounted for the elevated IR in HCV-infected subjects. The adipocytokines were not associated with histological features of chronic HCV infection except for TNFalpha which correlated with portal/periportal inflammation. HCV-associated IR is most likely an adipocytokine-independent effect of the virus to modulate insulin sensitivity.

Topics: Adiponectin; Adult; Biopsy; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Insulin Resistance; Interleukin-6; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged; Patient Selection; Reference Values; Tumor Necrosis Factor-alpha; Viral Load

Pretreatment with a low dose of bacterial endotoxin (lipopolysaccharide, LPS) caused the reduction of cytochrome P450 (CYP) enzymes and inflammatory factors which are capable of protecting the liver from a lethal LPS challenge. However, the effects of LPS pretreatment on the expression of transforming growth factor beta1 (TGFbeta1) and leptin in thioacetamide (TAA)-induced liver fibrosis remain unknown. In this study, Sprague-Dawley rats were pretreated intraperitoneally with LPS (5 mg/kg body weight) for 24 h, and subsequently treated with TAA (200 mg/kg body weight/ 3 days) for 1 month to examine the effects of LPS on TAA-injured rats. LPS pretreatment was associated with lower granulation and lower (P < 0.05) GOT/GPT than in TAA-injured rats. The LPS-pretreated group had less collagen (Sirius red histochemical staining). Semiquantitative RT-PCR showed that the levels of collagen 3 and TGFbeta1 mRNAs were lower (P < 0.05) in the liver of LPS-pretreated rats than in TAA-injured rats. TGFbetaRI mRNA in the liver of LPS-pretreated rats exceeded (P < 0.05) that in TAA-injured rats. LPS pretreatment reduced the leptin content (Western blot) below that of TAA-injured rats. These results imply that LPS pretreatment (endotoxin tolerance) alleviates the TAA-induced liver fibrosis of rats by reducing TGFbeta1 and leptin content.

Topics: Animals; Collagen Type III; Down-Regulation; Histocytochemistry; Immunohistochemistry; Leptin; Lipopolysaccharides; Liver Cirrhosis; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thioacetamide; Transforming Growth Factor beta1

Protein-calorie malnutrition is a common complication in cirrhosis. Protein restriction for the treatment of hepatic encephalopathy (HE) may cause disease progression and poor prognosis. Therefore, we evaluated important clinical parameters for nutritional state in cirrhotic patients with or without HE to predict the development of HE.. Twenty-two cirrhotic patients were divided into two groups; group A-13 patients without HE and group B-9 patients with HE. Clinical and biochemical parameters, serum proteins {serum albumin, insulin-like growth factor-1 (IGF-1), transferrin, leptin, etc}, immunologic parameters and anthropometry were measured.. Child-Pugh score and Model for End-stage Liver Disease (MELD) scale were higher in group B (p<0.01). After correction of various factors affecting nutritional assessment, especially of Child-Pugh score and MELD scale, leptin was higher in group B (p<0.05). There was no difference in anthropometric measurements. Transferrin correlated inversely with MELD scale in group A (p<0.01). IGF-1 correlated inversely with total lymphocyte count in group B (p<0.05). Leptin correlated with Child-Pugh scores, total lymphocyte count and mid-arm muscle circumference in group A (p<0.05, p<0.05 and p<0.05, respectively), and correlated inversely with CD8 in group B (p<0.05).. Leptin level is higher in patients with HE, and further studies for parameters of nutrition to predict HE in many cirrhotic patients will be needed.

Topics: Aged; Anthropometry; Biomarkers; Female; Hepatic Encephalopathy; Humans; Insulin-Like Growth Factor I; Leptin; Liver Cirrhosis; Male; Middle Aged; Nutritional Status; Transferrin

The aim of this study was to find a non-invasive marker, which could predict liver fibrosis without the need of liver biopsy in non-alcoholic steatohepatitis (NASH).. Fifty patients were included. All patients had one or more conditions that characterize the metabolic syndrome and histological proven NASH. Hyaluronic acid (HA), leptin (LT) and laminin (LN) were determined from serum withdrawn at the day of biopsy.. Patients were divided into two groups according to the histological findings. The first group consisted of 23 patients with NASH and fibrosis and the second group had 27 patients with NASH, ballooned cells, without fibrosis. Subjects with NASH and fibrosis had statistically significantly higher HA and LN than those with NASH without fibrosis, P<0.001, respectively. In contrast, there was no statistically significant difference between the levels of serum LT in the two groups. The stage of liver fibrosis in the 23 patients of group 1 was related only to the values of hyaluronic acid (P<0.001) and not to the ones of LT and LN.. Measurement of hyaluronic acid could be a predictive factor of the presence and stage of liver fibrosis in NASH. LN could be used to diagnose liver fibrosis but has no value in staging.

Topics: Adult; Aged; Biomarkers; Disease Progression; Fatty Liver; Female; Humans; Hyaluronic Acid; Laminin; Leptin; Liver Cirrhosis; Male; Middle Aged; Predictive Value of Tests; Prognosis

The main aim of this study was to examine the relationship of the leptin system in steatosis and nonalcoholic steatohepatitis (NASH). The study also analysed the pathogenic role of the leptin system in the development of hepatic fibrosis and its relation with the TGF-beta1 system.. The study included 90 subjects, 55 with NASH and 35 with simple steatosis. Gene expression of leptin, leptin receptor and TGF-beta mRNA was analysed by real-time PCR on liver tissue. Leptin serum levels were determined by RIA. Leptin receptor expression was also assessed by immunohistochemistry.. Increased expression was found for leptin receptor mRNA (P=0.0016) and its protein (P<0.05) in patients with NASH, especially those with fibrosis. There was a marked increase in gene expression of TGF-beta1 in patients with NASH (P=0.0002). A strong correlation was demonstrated between leptin receptor gene expression and TGF-beta1 gene expression (P=0.023). No leptin expression was found in the liver tissue. All patients showed a marked hyperleptinemia, which was closely related to the anthropometric characteristics analysed and independent of development or not of NASH.. The results of the study demonstrate for the first time increased leptin receptor expression in liver tissue and its relationship with overexpression of TGF-beta1 and the degree of hepatic fibrosis.

Topics: Adult; Fatty Liver; Female; Gene Expression; Humans; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Severity of Illness Index; Transforming Growth Factor beta1

Malnutrition, a common problem in liver cirrhosis and HCC, may readily deteriorate the clinical functions with resultant poor prognosis. Beside the hyper catabolic state frequently encountered in chronic liver disease and HCC, anorexia and reduced food intake also worsen the malnutrition. The recently discovered peptide hormone ghrelin acts as a counterpart of leptin in regulation of food intake and fat utilization. The aim of the present study was to investigate the ghrelin and leptin levels in cirrhosis and HCC due to hepatitis B and D viruses, and the association of ghrelin and leptin with TNF-alpha, IL-6 and the severity of the disease.. We measured serum ghrelin, leptin, TNF-alpha, and IL-6 levels using specific immunoassay in 45 patients (23 cirrhosis, 22 HCC) with HBV and/or HDV and in 25 control subjects.. In comparison to controls, serum ghrelin, TNF-alpha, and IL-6 levels were significantly higher in cirrhosis and HCC (P < .05), whereas serum leptin levels were found decreased (P < .05). There was a positive correlation between ghrelin and TNF-alpha, and a negative correlation between leptin and TNF-alpha (P < .05).. In cirrhosis and HCC due to HBV or HDV, serum ghrelin levels were increased with a corresponding decrease in serum leptin concentrations, acting as a physiological counterpart of ghrelin. The increasing of ghrelin is more prominent in Child C cirrhosis and the level was correlated with TNF-alpha. The presence of nutritional and metabolic abnormalities, including malnutrition, in cirrhosis and HCC may, at least partly, elucidate high ghrelin and low leptin levels.

Topics: Adult; Aged; Biomarkers; Carcinoma, Hepatocellular; Female; Ghrelin; Hepatitis B; Hepatitis D; Humans; Immunoassay; Interleukin-6; Leptin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Peptide Hormones; Tumor Necrosis Factor-alpha

Prevalence of non-alcoholic fatty liver disease (NAFLD) among children is increasing dramatically. It is unclear why some patients develop steatohepatitis (NASH), fibrosis and cirrhosis from steatosis, and others do not. A role for leptin has been claimed. This study aims to evaluate the relationship between leptin, insulin resistance (IR) and NAFLD in children.. In 72 biopsy-proven NAFLD children (aged 9-18 years; 51M/21F), fasting leptin and its soluble receptor (sOB-R) were measured; free leptin index (FLI) was calculated as leptin/sOB-R; IR was estimated by homeostasis model assessment (HOMA-IR) and insulin sensitivity index (ISI-comp); glucose tolerance by oral glucose tolerance test (OGTT). Percentage of total body fat (TBF) by dual-energy X-ray absorptiometry (DXA) was available in 65 patients.. Prevalence of diabetes, impaired fasting and/or after load glucose tolerance was 11%. HOMA-IR and ISI-comp values were 2.55 +/- 1.39 and 4.4 +/- 2. NASH was diagnosed in 38 and simple steatosis in 25 children; diagnosis was indeterminate in 29 children. Increased fibrosis, mostly of mild severity, was observed in 41 patients. Median NAFLD activity (NAS) score was 3.42 +/- 1.60. According to histology, levels of leptin and FLI increased as steatosis (leptin from 11.9 +/- 6.3 in score 1 to 17.4 +/- 6.9 in score 2 (P = 0.01) and 22.2 +/- 6.8 ng/ml in score 3 (P < 0.001); FLI 2.56 +/- 1.40, 3.57 +/- 0.34, 4.45 +/- 0.64 respectively (P = 0.05)); ballooning (from 13.7 +/- 6.7 in score 1 to 17 +/- 7.5 in score 2 (P = 0.001) and 22.1 +/- 7.1 ng/ml in score 3 (P = 0.01); FLI 2.81 +/- 1.50, 3.40 +/- 1.65, 4.57 +/- 1.67 (P = 0.01 between 0 and 2)); fibrosis (from 14.3 +/- 7 to18.3 +/- 6.9; P = 0.03; FLI 3.03 +/- 1.57 vs 3.92 +/- 077; P < 0.05) and NAS score (score 1-2: 12.9 +/- 6.9; score 3-4: 17 +/- 6.9 (P = 0.01); score 5-7: 22.9 +/- 7.5 ng/ml (P = 0.03); FLI 2.70 +/- 1.53, 3.12 +/- 1.53, 4.58 +/- 1.57 P = 0.01 and P = 0.05 between 1-2 vs 3-4 and 3-4 vs 5-7 respectively) worsened. Higher leptin correlated with more severe steatosis, ballooning and NAS score (r(0) = 0.6, 0.4 and 0.6 respectively; for all P < 0.001); FLI with ballooning (r(0) = 0.4, P < 0.0001), steatosis (r(0) = 0.5, P < 0.0001) and NAS score (r(0) = 0.5, P < 0.0001).. Leptin and liver injury correlated independently of age, BMI and gender in the present study. Nevertheless, any causative role of leptin in NAFLD progression could be established. Thus, studies are needed to define whether the hormone plays a major role in the disease.

Topics: Adolescent; Child; Cohort Studies; Fatty Liver; Female; Humans; Insulin Resistance; Italy; Leptin; Liver; Liver Cirrhosis; Male; Prevalence

Although serum leptin concentrations are reported by several studies to increase in patients with liver cirrhosis, the mechanisms underpinning this increase remain unclear. Circulating tumor necrosis factor alpha (TNF-alpha) concentrations are also recognized to increase in liver cirrhosis. Furthermore, TNF-alpha administration to rodents results in increased expression and secretion of leptin from adipose tissue in a manner dependent on type 1 TNF-alpha receptor (TNF-RI). The present study was undertaken to examine adipose leptin expression and to explore potential relationships between leptin expression and TNF-alpha in subjects with liver cirrhosis. Liver cirrhosis was induced in male Sprague-Dawley rats by dimethylnitrosamine (DMN) administration or by common bile duct ligation (BDL). Ad libitum and pair-fed animals constituted controls. Serum leptin and TNF-alpha concentrations were determined by immunoassay. Gene expression was determined by the reverse transcription-polymerase chain reaction, and protein levels were measured by Western blotting. Serum leptin values after adjustment of body fat mass in DMN-treated rats were significantly higher than in pair-fed or ad libitum groups. Leptin mRNA and protein levels in epididymal fat in DMN rats increased by 1.8-fold and 2.3-fold, respectively, as compared with ad libitum controls, and by 4-fold and 6-fold, respectively, as compared with the pair-fed group. Epididymal TNF-alpha and membranous TNF-RI (mTNF-RI) concentrations were both 2.3 times higher in DMN rats than in ad libitum controls but did not differ between ad libitum and pair-fed groups. Adipose leptin protein levels correlated directly with TNF-alpha and mTNF-RI concentrations in combined DMN, ad libitum, and pair-fed rats (r=0.64 and r=0.49, respectively; P<.05). In BDL-treated rats, however, serum and adipose leptin concentrations were identical to those in ad libitum controls despite 2.1-fold and 2.4-fold increase in epididymal TNF-alpha and mTNF-RI, respectively. TNF-alpha administration to fasting control animals increased serum and adipose leptin concentrations significantly. The observed TNF-alpha-associated leptin up-regulation in DMN-induced, but not in BDL-induced, cirrhotic rats is consistent with distinctly different roles for TNF-alpha in rats with nonbiliary, as opposed to biliary, cirrhosis.

Topics: Adipose Tissue; Animals; Bile Ducts; Bilirubin; Blotting, Western; Dimethylnitrosamine; Eating; Epididymis; Gene Expression; Immunoassay; Leptin; Ligation; Liver; Liver Cirrhosis; Male; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

Although leptin is a key adipokine promoting liver fibrosis, adiponectin may prevent liver injury. To determine the role of these adipokines in liver fibrosis and to understand their expression in vivo, fa/fa rats and their lean littermates were subjected to bile duct ligation (BDL). Histomorphometry for collagen and alpha-smooth muscle actin (alpha-SMA) revealed that lean rats, but not fa/fa littermates, had significant fibrosis with abundant hepatic stellate cell (HSC) activation. The lean-BDL rats had significantly higher leptin concentrations in the hepatic vein than lean sham-operated, fa/fa BDL, or fa/fa sham-operated rats. Co-localization of leptin and alpha-SMA in activated HSCs was observed by immunohistochemistry. Real-time reverse transcriptase-polymerase chain reaction and Western blot analysis confirmed the presence of leptin and alpha-SMA in activated, but not quiescent, HSCs, whereas only quiescent HSCs synthesized adiponectin mRNA and protein. Adiponectin overexpression in activated HSCs reduced proliferation, augmented apoptosis, and reduced expression of alpha-SMA and proliferating cell nuclear antigen. Adiponectin receptors (AdipoR1 and AdipoR2) were detected in both activated and quiescent HSCs, but only activated HSCs produced significant apoptosis after treatment with either globular or full-length adiponectin. Adiponectin may act to reverse HSC activation, maintain HSC quiescence, or significantly, may have important therapeutic implications in liver fibrosis.

Topics: Actins; Adiponectin; Animals; Apoptosis; Bile Ducts; Blotting, Western; Disease Models, Animal; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Leptin; Ligation; Liver; Liver Cirrhosis; Obesity; Rats; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction

Nonalcoholic steatohepatitis is prevalent among obese individuals with excessive caloric intake, insulin resistance, and type II diabetes. However, no animal models exist that recapitulate this important association. This study produced and characterized steatohepatitis (SH) caused by intragastric overfeeding in mice. C57BL/6, tumor necrosis factor (TNF) type I receptor-deficient, and genetically matched wild type mice were fed via an implanted gastrostomy tube a high-fat diet for 9 weeks in the increasing amount up to 85% in excess of the standard intake. Animals were examined for weight gain, insulin sensitivity, and histology and biochemistry of liver and white adipose tissue (WAT). Overfed C57BL/6 mice progressively became obese, with 71% larger final body weights. They had increased visceral WAT, hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance, and insulin resistance. Of these mice, 46% developed SH with increased plasma alanine aminotransferase (121 +/- 27 vs. 13 +/- 1 U/L), neutrophilic infiltration, and sinusoidal and pericellular fibrosis. Obese WAT showed increased TNFalpha and leptin expression and reciprocally reduced adiponectin expression. The expression of lipogenic transcription factors (SREBP-1c, PPARgamma, LXRalpha) was increased, whereas that of a lipolytic nuclear factor PPARalpha was reduced in SH. SH was associated with reduced cytochrome P450 (Cyp)2e1 but increased Cyp4a. TNF type I receptor deficiency did not prevent obesity and SH. In conclusion, forced overfeeding with a high-fat diet in mice induces obesity, insulin resistance, and SH in the absence of TNF signaling or Cyp2e1 induction.

Topics: Alanine Transaminase; Animals; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP4A; Dietary Fats; Disease Models, Animal; Eating; Fatty Liver; Gastrostomy; Glucose Intolerance; Insulin Resistance; Leptin; Liver Cirrhosis; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Obesity; PPAR alpha; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha

Leptin upregulates collagen expression in hepatic stellate cells (HSCs), but the possible modulation of other actions has not been elucidated. The aim of this study was to investigate the expression and function of leptin receptors (ObR) in human HSCs and the biological actions regulated by leptin. Exposure of HSCs to leptin resulted in upregulation of monocyte chemoattractant protein 1 (MCP-1) expression. Leptin also increased gene expression of the proangiogenic cytokines vascular endothelial growth factor (VEGF) and angiopoietin-1, and VEGF was also upregulated at the protein level. Activated HSCs express ObRb and possibly other ObR isoforms. Exposure to leptin increased the tyrosine kinase activity of ObR immunoprecipitates and resulted in activation of signal transducer and activator of transcription 3. Several signaling pathways were activated by leptin in HSCs, including extracellular-signal-regulated kinase, Akt, and nuclear factor kappaB, the latter being relevant for chemokine expression. Leptin also increased the abundance of hypoxia-inducible factor 1alpha, which regulates angiogenic gene expression, in an extracellular-signal-regulated kinase- and phoshatidylinositol 3-kinase-dependent fashion. In vivo, leptin administration induced higher MCP-1 expression and more severe inflammation in mice after acute liver injury. Conversely, in leptin-deficient mice, the increase in MCP-1 messenger RNA and mononuclear infiltration was less marked than in wild-type littermates. Finally, ObR expression colocalized with VEGF and alpha-smooth muscle actin after induction of fibrosis in rats. In conclusion, ObR activation in HSCs leads to increased expression of proinflammatory and proangiogenic cytokines, indicating a complex role for leptin in the regulation of the liver wound-healing response.

Topics: Cells, Cultured; Chemokine CCL2; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; JNK Mitogen-Activated Protein Kinases; Leptin; Liver; Liver Cirrhosis; NF-kappa B; Proto-Oncogene Proteins c-akt; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Up-Regulation; Vascular Endothelial Growth Factor A; Wound Healing

Topics: Fatty Liver; Humans; Insulin Resistance; Leptin; Liver; Liver Cirrhosis; Metabolic Syndrome

To construct the specific siRNA expression vectors and investigate their effect on leptin and collagen I in HSC, which provide a new approach to the prevent and treat hepatic fibrosis. The five siRNAs against leptin gene were transcript synthesized intracellularly by expression templates of plasmid vector psiRNA-hH1neo. The recombinant leptin siRNA plasmid vectors could express in eukaryocyte, and then to evaluate them by using enzyme cutting and sequencing. The recombinant plasmids were transfected into HSCs using Lipofectamine methods respectively. The cells were selected after growing in DMEM containing 300 microg/mL G418 for about 4 weeks. Gene expression of leptin and collagen I were showed by Western blot analysis and reverse transcription polymerase chain reaction (RT-PCR). Identification by enzyme cutting and sequencing showed that the leptin siRNA expression vectors were constructed successfully, and leptin siRNA could inhibit the leptin and collagen I gene expression effectively. It was concluded that RNA interference-mediated silencing of leptin gene diminished leptin and collagen I gene expression in HSCs. Furthermore, attenuated the extracellular matrix over-deposition at the same time. Leptin gene is ideal targets of gene therapy for liver fibrosis.

Topics: Cell Line; Collagen Type I; Gene Targeting; Genetic Therapy; Leptin; Liver; Liver Cirrhosis; RNA, Small Interfering

Recent attention has focused on the liver profibrogenic role of leptin in animal models. The purpose of this study was to evaluate the role of leptin and TNF-alpha in the severity of liver fibrosis in patients with chronic hepatitis C (CHC). We used a radioimmunoassay to determine serum leptin concentrations in 77 consecutive patients with CHC and 22 healthy controls. Leptin was correlated with liver histological (METAVIR) and metabolic indices. Sixty five patients had none to moderate liver fibrosis (F0-F2) and twelve severe fibrosis (F3-F4). Steatosis was observed in all but 27 patients. Leptin was significantly increased in patients compared with controls and was significantly more elevated in females both in patients and controls. The age, age at infection, prothrombin index, body mass index (BMI), triglycerides, glycaemia, ferritin, leptin and TNF-alpha, were associated with severe fibrosis. Steatosis was significantly more pronounced in patients with severe than those without or moderate fibrosis (P = 0.04). Only leptin was significantly and independently associated with severe fibrosis (OR = 1.2, CI 95%: 1.1-1.4, P = 0.03). Leptin was significantly associated with BMI (r = 0.64, P < 0.001) and glycaemia (r = 0.43, P < 0.001). Significant correlations were found between steatosis and BMI (r = 0.30, P < 0.01) and glycaemia (r = 0.30, P < 0.01). In patients with CHC and higher BMI and glycaemia levels, the severity of liver fibrosis is associated with serum leptin. TNF-alpha is a putative candidate involved in the mechanism.

Topics: Adolescent; Adult; Case-Control Studies; Fatty Liver; Female; Hepatitis C, Chronic; Humans; Leptin; Liver; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Severity of Illness Index; Tumor Necrosis Factor-alpha

Leptin is involved in the regulation of food intake and is mainly secreted by adipocytes. Major secretagogues are cytokines such as TNF-alpha or IL-1. Leptin in turn upregulates inflammatory immune responses. Elevated leptin serum levels have been detected in patients with liver cirrhosis, a disease frequently associated with elevated levels of circulating cytokines as well as hypermetabolism and altered body weight. Recently, leptin has been detected in activated hepatic stellate cells in vitro and an involvement of leptin in liver fibrogenisis has been suggested. The current study was designed to further clarify the role of leptin in liver disease by characterizing leptin and leptin receptor expression in the development and onset of experimental liver fibrosis. Liver fibrosis and cirrhosis was induced in rats by use of phenobarbitone and increasing doses of CCl (4). Leptin and leptin receptor mRNA expression was determined by semiquantitative RT-PCR, protein expression by Western blot analysis and localization of leptin and its receptor by immunohistochemistry. Normal liver tissue does not express leptin, but leptin receptor mRNA. Increasing levels of leptin mRNA were detected in fibrotic and cirrhotic livers correlated to the degree of fibrosis. Leptin receptor mRNA expression was not significantly altered in damaged livers. Increasing levels of leptin were detected in fibrotic and cirrhotic livers, whereas protein expression of the receptor remained unchanged. Throughout different stages of liver fibrosis, leptin immunoreactivity was localized in activated hepatic stellate cells only, whereas immunoreactivity for the receptor was mainly seen on hepatocytes. In conclusion, leptin is expressed at increasing levels in activated hepatic stellate cells in vivo, which may therefore be a source of increased leptin tissue and serum levels contributing to the pathophysiology and morphological changes of chronic liver disease.

Topics: Animals; Blotting, Western; Carbon Tetrachloride; Gene Expression Regulation; Immunohistochemistry; Leptin; Liver Cirrhosis; Liver Cirrhosis, Experimental; Male; Phenobarbital; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Leptin is an adipocyte-derived hormone involved in the homeostasis of body composition. An imbalance in leptin regulation has been observed in patients with liver cirrhosis. We aimed to assess serum and ascitic leptin levels in a group of patients with decompensated liver cirrhosis and to evaluate the relationship of these levels with tumor necrosis factor alpha (TNF-alpha). We assessed both serum and ascitic fluid leptin levels in a series of 16 consecutive patients with liver cirrhosis. We calculated the body mass index (BMI) and assessed body fat (BF) of all patients by means of bioelectric impedence analysis. Leptin levels were analyzed in relationship to biochemical indexes, TNF-alpha levels, and body composition. None of the patients had spontaneous bacterial peritonitis. Both serum and ascites leptin levels were correlated with BMI and BF. On average, ascitic fluid leptin levels (13.1 +/- 10.9 ng/ml) were twice as high as serum levels (7.0 +/- 6.4 ng/ml), and the ascitic fluid/serum ratio of leptin was > 1 in all patients. Serum and ascites leptin levels were positively correlated (rS = 0.675, P = 0.009), while no correlation was observed between leptin and TNF-alpha levels, both in serum and in ascites. Serum and ascites TNF-alpha were not correlated. The ascitic fluid leptin levels of cirrhotic patients with sterile ascites are on average two times higher than circulating levels of this hormone. Noteworthily, they correlate significantly with body composition. These findings seem to suggest that in patients with decompensated liver cirrhosis, intraabdominal production of leptin may contribute to the metabolic picture.

Topics: Adipose Tissue; Aged; Ascites; Ascitic Fluid; Body Composition; Body Mass Index; Electric Impedance; Female; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Prospective Studies; Tumor Necrosis Factor-alpha

Data from animal models of fibrosis and fatty liver suggest that leptin may mediate the profibrogenic responses in the liver, but the association of leptin and liver fibrosis in human nonalcoholic fatty liver disease (NAFLD) remains undefined. We aimed at determining the relation between leptin and liver fibrosis in human NAFLD.. Human plasma leptin and several indicators of insulin resistance were measured in 88 NAFLD patients and matched controls.. Leptin levels were significantly greater in patients with more advanced fibrosis (P = 0.005). By multivariate analysis, the significant association between leptin and fibrosis was abolished (adjusted P = 0.3) when controlling for confounders including age, gender, BMI, diabetes and insulin resistance. Only age (adjusted P = 0.006) and insulin sensitivity (adjusted P = 0.04) correlated significantly with fibrosis stage. A second liver biopsy was performed in 39 out of the 88 patients at 27.9 +/- 16 months. Leptin levels were not significantly different between patients who had fibrosis progression (n = 10) and those who did not (n = 29).. In human NAFLD, no relationship between leptin levels and fibrosis stage was demonstrated. The correlation of leptin and fibrosis severity seems to be an indicator of the factors that determine leptin production.

Topics: Adult; Aged; Aging; Case-Control Studies; Disease Progression; Fatty Liver; Female; Humans; Insulin Resistance; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged

Topics: Body Mass Index; Clinical Trials as Topic; Fats; Fatty Liver; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Leptin; Liver; Liver Cirrhosis; Male; Sex Factors

Hepatic steatosis (HS) has been related to obesity and fibrosis in chronic hepatitis C (CHC). The aim of this study was to determine the role of leptin system in HS development.. Patients (n = 131) with biopsy-proven CHC, positive HCV RNA, and raised ALT were enrolled. Body mass index, percentage of body fat by skin fold measurement, and bioelectrical impedance analysis was calculated and serum leptin concentration measured. Intrahepatic HCV RNA, HS, necroinflammatory activity, and fibrosis were determined in liver biopsy tissue.. HS was present in 63 patients (48.1%). Steatosis was evident in 32 of 91 patients (35.2%) infected with genotype 1 and in 22 of 27 patients (81.5%) with genotype 3a (p < 0.001). In patients infected by genotype 3a, HS correlated significantly with intrahepatic HCV RNA load (r = 0.78; p < 0.001). However, in genotype 1, HS was associated with host factors such as leptin, body mass index, percentage of body fat, and visceral obesity. Multivariate analysis showed genotype (OR = 11.54, 95% CI = 1.13-117.14, p = 0.038), leptin levels (OR = 1.09, 95% CI = 1.03-1.17, p = 0.008) and fibrosis (OR = 9.86, 95% CI = 2.11-5.86, p = 0.03) as independent variables of HS development.. Hepatic steatosis was related to genotype, fibrosis degree, and serum leptin levels. Genotype 3 seems to have a viral specific steatogenic effect. Leptin seems to be a link between obesity and steatosis development in CHC genotype 1-infected patients.

Topics: Adult; Alcohol Drinking; Body Mass Index; Clinical Trials as Topic; Fatty Liver; Female; Fibrosis; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Leptin; Liver Cirrhosis; Liver Function Tests; Male; Multivariate Analysis; Polymerase Chain Reaction; Regression Analysis; RNA, Viral; Viral Load

The aim of the present study was to investigate serum leptin levels in relation to anthropometric features in patients with liver cirrhosis (LC) and chronic viral hepatitis (CVH), and to determine the effect of the severity and aetiology of the LC on serum leptin levels.. Forty-nine patients with LC, 32 patients with CVH and 69 control subjects were age, body mass index (BMI) and sex-matched and included in the study. Plasma glucose, serum leptin and insulin levels were determined. Insulin resistance was assessed using homoeostasis model assessment (HOMA). Body composition was estimated by skinfold thickness.. Female patients with Child-A LC had higher levels of leptin, and female and male patients with Child-A LC had higher absolute leptin (leptin/BFM) levels compared to patients with Child-C LC and control subjects. Serum leptin levels of the patients with alcohol LC were higher than the control subjects, but the absolute leptin levels were comparable. When alcoholic and post-viral hepatitis cirrhotic patients were compared with each other on an aetiologic basis, there was no significant difference between them in leptin and absolute leptin levels. There were significant correlations between leptin and BMI, body fat percentage (BFP), BFM (body fat mass) in all three groups in both sexes.. These data suggest that the physiologic correlations among serum leptin level, sex, BMI and BFM were well preserved in patients with chronic liver disease. Patients with alcohol LC had higher leptin levels. In early stages of liver disease, leptin levels and absolute leptin levels are higher than in normal subjects. However, in advanced stages of the disease the significant decline in leptin levels and similar levels of leptin expressed in relation to BFM compared to control subjects predominantly represent the expression of fat mass.

Topics: Adult; Aged; Anthropometry; Blood Glucose; Body Mass Index; Female; Hepatitis, Chronic; Hepatitis, Viral, Human; Humans; Hypoglycemic Agents; Insulin; Leptin; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Risk Factors; Severity of Illness Index

Leptin's actions on certain cells require a leptin-inducible neurotransmitter, norepinephrine (NE). NE modulates hepatic fibrosis. Therefore, decreased NE may explain why leptin deficiency inhibits hepatic fibrosis. We manipulated adrenergic activity in leptin-deficient ob/ob mice, leptin-sufficient, dopamine beta-hydroxylase deficient (Dbh(-/-)) mice, and HSC cultures to determine if leptin requires NE to activate HSC and induce hepatic fibrosis. ob/ob mice have chronic liver injury, but reduced numbers of HSC. Supplemental leptin increases HSC, suggesting that leptin-dependent, injury-related factors permit expansion of HSC populations. NE also increases HSC numbers and activation, normalizing fibrogenesis. When fed hepatotoxic diets, NE-deficient Dbh(-/-) mice fail to accumulate activated HSC and have impaired fibrogenesis unless treated with adrenergic agonists. NE acts directly on HSC to modulate leptin's actions because leptin increases HSC proliferation and prazosin, an alpha-adrenoceptor antagonist, inhibits this. Thus, leptin permits injury-related increases in adrenergic activity and requires NE to activate HSC and induce hepatic fibrogenesis.

Topics: Adrenergic Agonists; Animals; Cell Count; Cells, Cultured; Collagen; Dopamine beta-Hydroxylase; Epinephrine; Gene Expression; Leptin; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Norepinephrine; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System; Transforming Growth Factor beta; Transforming Growth Factor beta1

This study was conducted to investigate whether leptin is involved in the etiogenesis of hepatocellular carcinoma (HCC) in cirrhotic patients.. Thirty-one male cirrhotic patients with HCC, 26 male cirrhotic patients without HCC, and 25 control subjects were included in this study. Body fat mass (FM) was determined by bioelectrical impedance analysis, and serum leptin and hormone concentrations were measured by immunoassay.. A significant correlation of serum leptin levels to FM was observed in both patient groups and control subjects (r = 0.760, p < 0.001; r = 0.520, p < 0.01; r = 0.460, p < 0.05, respectively). The serum leptin levels in cirrhotic patients with or without HCC were significantly higher than those in control subjects (6.0 +/- 1.1 vs. 6.1 +/- 0.6 vs. 3.8 +/- 0.3 ng/ml, p < 0.05), though their body FM was lower. Using a multiple logistic regression analysis, it was found that the odds ratio of serum leptin for HCC was 1.04 (95% CI 0.79-1.33) after adjustment of several known risk factors.. Our study demonstrated that cirrhotic patients with or without HCC had increased serum leptin concentrations. However, leptin did not appear to be associated with the development of HCC in cirrhotic patients.

Topics: Aged; Carcinoma, Hepatocellular; Humans; Leptin; Liver Cirrhosis; Liver Neoplasms; Logistic Models; Male; Middle Aged; Odds Ratio

Increased leptin levels in patients with liver cirrhosis are postulated to result in malnutrition and increased energy expenditure. Since cirrhotic patients show improved nutritional status after a transjugular intrahepatic portosystemic stent shunt (TIPS), it was the aim of this study to evaluate plasma leptin levels and their influence on nutritional status prior to and after the TIPS procedure. We evaluated plasma leptin levels, body mass index (BMI), Child-Pugh score and pertinent biochemical parameters in 31 patients (19 men and 12 women) with severe complications of liver cirrhosis (74% ethyltoxic men, 50% ethyltoxic in women), prior to and after TIPS. Nineteen cirrhotic patients without TIPS served as controls. In women ascitic-free BMI significantly increased (from 22.8 +/- 4.6 kg/m2 to 23.9 +/- 4.9; p = 0.004 three months after TIPS), whereas in men only a tendency toward higher values (26.1 +/- 4.7 vs. 26.7 +/- 4.4; p = 0.28) was found. Analysis of peripheral venous leptin concentrations before and three months after TIPS revealed a significant increase in women (11.9 +/- 8.8 ng/ml vs. 18.6 +/- 14.9; p = 0.009) and in men (7.7 +/- 6.2 ng/ml vs. 12.2 +/- 9.0; p = 0.005). In addition, the leptin-BMI ratio increase significantly in women and men three months after TIPS implantation (women 0.49 +/- 0.29 vs. 0.73 +/- 0.52; p = 0.017; men 0.28 +/- 0.22 vs. 0.43 +/- 0.28; p = 0.002). On the other hand, patients without TIPS implantation showed no significant alterations of BMI and peripheral venous leptin concentrations. After TIPS implantation in liver cirrhotic patients, leptin levels were increased and the nutritional status improved. Therefore, our analysis suggests that in patients with predominantly ethyltoxic liver cirrhosis, elevated leptin levels are not a major reason for poorer body composition.

Topics: Adipose Tissue; Adult; Aged; Body Mass Index; Female; Humans; Insulin; Leptin; Liver Cirrhosis; Liver Function Tests; Male; Malnutrition; Middle Aged; Nutritional Status; Portasystemic Shunt, Transjugular Intrahepatic; Statistics, Nonparametric

Topics: Humans; Leptin; Liver Cirrhosis; Liver Diseases, Alcoholic; Male; Transforming Growth Factor beta; Transforming Growth Factor beta1

Host factors such as increased body mass index (BMI) and genotype-specific viral factors contribute to the development of steatosis in patients with chronic hepatitis C (HCV). We hypothesized that host metabolic factors associated with increased BMI may play a role in disease progression.. Fasting serum was collected from 160 patients with chronic HCV at the time of liver biopsy and 45 age, gender and BMI matched controls, and assessed for levels of insulin, c-peptide and leptin.. Patients with viral genotype 3 had more severe steatosis (P=0.0001) and developed stages 1 and 2 fibrosis at a younger age (P<0.05) than patients with genotype 1. For both genotypes, overweight patients had significantly more steatosis and increased insulin and leptin levels. In contrast to lean patients, there was a statistically significant increase in circulating insulin levels with increasing fibrosis in overweight patients with chronic HCV (P=0.03). Following multivariate analysis, insulin was independently associated with fibrosis (P=0.046) but not inflammation (P=0.83). There was no association between serum leptin levels and stage of fibrosis.. Increasing circulating insulin levels may be a factor responsible for the association between BMI and fibrosis in patients with HCV, irrespective of viral genotype.

Topics: Adult; Body Mass Index; Fatty Liver; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Insulin; Leptin; Liver Cirrhosis; Male; Middle Aged; Obesity

Obesity is associated with hyperleptinemia and is also a risk factor for fibrosis and severity of fibrosis in several chronic liver diseases. The correlation between increased leptin, obesity and hepatic fibrosis prompted us to hypothesise that leptin has profibrogenic effects on the liver.. We analysed the role of leptin in liver fibrosis in leptin-deficient mice fed a diet which generates steatohepatitis, and in chronic carbon tetrachloride-induced hepatic injury.. Leptin-deficient mice failed to develop fibrosis during steatohepatitis or in response to chronic toxic liver injury, and failed to up-regulate collagen-I while developing similar hepatic injury as their genetic controls. Restitution of physiological levels of circulating leptin by injection of exogenous leptin, but not correction of the obese phenotype by dietary manipulation, restored liver fibrosis in leptin-deficient mice during chronic liver injury. These results confirmed the absolute requirement of leptin for hepatic fibrosis. We showed that leptin deficiency did not alter hepatic TNF regulation but that leptin is necessary for induction of bioactive transforming growth factor beta 1 (TGFbeta1) protein in the context of chronic liver injury.. These data establish that leptin is an essential mediator of hepatic fibrosis in response to chronic liver injury, whether metabolic or toxic in aetiology.

Topics: Animals; Carbon Tetrachloride; Chronic Disease; Disease Progression; Fatty Liver; Female; Leptin; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxidative Stress; Phenotype; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The aim of this study was to examine the possible relationship between the plasma levels of leptin and tumor necrosis factor (TNF)-alpha and the stage of hepatic fibrosis in a cohort of patients with chronic hepatitis C. Leptin and TNF levels were measured by RIA in 135 patients and in 75 age- and sex-matched controls. Liver disease was evaluated by the stage of fibrosis and the extent of inflammatory infiltrate in the liver biopsy. Leptin levels correlated with BMI values in healthy controls and in patients with chronic hepatitis C (men, r = 0.61, P = 0.0001; women, r = 0.68, P = 0.003). Leptin levels increased as hepatic fibrosis stage progressed both in male and in female patients (P < 0.001); also, TNF levels were higher in patients with an advanced stage of fibrosis (P = 0.006). In these patients, levels of leptin increased according to the progression of the stage of fibrosis; these data suggest that leptin may play a role in the regulation of hepatic fibrosis.

Topics: Adult; Aged; Disease Progression; Female; Hepatitis C, Chronic; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged

Nonalcoholic steatohepatitis (NASH) is a disorder characterized by hepatic steatosis, inflammation, and fibrosis. Leptin is an adipocyte-derived antiobesity hormone that in rodents prevents "lipotoxicity" by limiting triglyceride accumulation and also regulates matrix deposition (fibrosis) during wound healing. We therefore determined serum leptin levels in patients with NASH to determine whether relationships existed between leptin levels and severity of hepatic steatosis or fibrosis. We used a radioimmunoassay to determine serum [total] leptin concentrations in 27 men and 20 women with NASH and 47 controls matched for gender and body mass index (BMI; and partly for age). Serum leptin values were correlated with hepatic steatosis, fibrosis, and inflammation (each categorized semiquantitatively on liver histology), and with anthropometric indices, serum lipids, glucose, insulin, c-peptide, and alanine aminotransferase (ALT) levels. Compared with the controls, mean serum leptin levels were raised in both men and women with NASH (men 14 +/- 11 ng/mL vs. 7.2 +/- 4.1 ng/mL, P =.003; women 35 +/- 16 ng/mL vs. 15 +/- 8.2 ng/mL, P <.001). Leptin values correlated with serum c-peptide levels but not with BMI. In a multivariate analysis, serum leptin (P =.027), serum c-peptide (P =.001), and age (P =.027) were selected as independent predictors of the severity of hepatic steatosis. However, serum leptin was not an independent predictor of hepatic inflammation or fibrotic severity. In conclusion, hyperleptinemia occurs in NASH and is not explained simply by gender, obesity, or the presence of type 2 diabetes. Furthermore, leptin levels correlate directly with the severity of hepatic steatosis but not with inflammation or fibrosis. We propose that the relationship between leptin and steatosis reflects a pathogenic role of leptin in hepatic insulin resistance and/or a failure of the antisteatotic actions of leptin ("peripheral leptin resistance").

Topics: Adult; Aged; C-Peptide; Fatty Liver; Female; Hepatitis; Humans; Insulin; Insulin Resistance; Leptin; Liver Cirrhosis; Male; Middle Aged; Multivariate Analysis; Severity of Illness Index; Sex Factors; Triglycerides

Several reports have documented the involvement of hyerleptinaemia in malnutrition associated with liver cirrhosis. However, the mechanisms of elevated leptin levels remains unclear. Serum concentrations of tumour necrosis factor-alpha (TNF-alpha), and two soluble TNF receptors (sTNF-RI and sTNF-RII) are increased in patients with liver cirrhosis. In rodents, administration of TNF-alpha has been shown to stimulate plasma leptin concentration, suggesting that a cytokine-leptin link may mediate anorexia and weight loss during chronic inflammation. In this study, we investigate the potential interaction of the TNF-alpha system with leptin in the development of malnutrition in liver cirrhosis.. A total of 26 male patients with liver cirrhosis and 25 healthy people were recruited at an outpatient clinic at the Veterans General Hospital in Taiwan. Serum biochemistry and anthropometric measurement by bioelectrical impedance analysis were used to assess nutrition status, and immunoassay was used to determine serum leptin, TNF-alpha sTNF-RI and sTNF-RII concentrations.. In cirrhotic patients, the body fat mass (FM) and serum albumin levels were both lower than control subjects [15.8 (13.2-19.5) kg vs. 18.9 (16.2-20.1) kg; 35 (33-41) g/l vs. 43 (41-45) g/l, respectively; P < 0.05]. Serum TNF-alpha sTNF-RI and sTNF-RII were significantly elevated in cirrhotic patients compared to healthy controls [9.8 (7.2-13.5) ng/l vs. 4.3 (3.4-7.3) ng/l; 1682.1 (1344.8-2179.4) ng/l vs. 1319.6 (1037.7-1632.1) ng/l; 4462.2 (3748.5-5159.4) ng/l vs. 3559.8 (2506.9-3988.9 ng/l, respectively; P < 0.01] and correlated with disease severity (graded by Pugh-Child's scores). An inverse correlation was observed between circulating sTNF-RI and sTNF-RII to serum albumin levels (r =-0.42, r = -0.398; P < 0.05). The serum leptin levels in cirrhotic patients were significantly higher [6.0 (3.6-7.7) (g/l vs. 3.4 (2.9-4.3) (g/l; P < 0.01) and correlated with body FM (r = 0.52; P < 0.01]. Using a multiple linear regression analysis with leptin as dependent variable and FM and TNF-alpha, sTNF-R as independent variables, FM and serum sTNF-RI concentrations were found to predict independently the leptin levels in cirrhotic patients.. Our study demonstrated that serum levels of TNF-alpha, sTNF-RI, sTNF-RII and leptin were all elevated in cirrhotic patients. The severity of liver cirrhosis was an important factor for the activation of TNF-alpha system. The activated TNF-alpha system conjointly with hyperleptinaemia might mediate malnutrition in patients with liver cirrhosis.

Topics: Aged; Antigens, CD; Body Composition; Case-Control Studies; Humans; Leptin; Linear Models; Liver Cirrhosis; Male; Middle Aged; Nutrition Disorders; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Serum Albumin; Tumor Necrosis Factor-alpha

Leptin is a 16-kd hormone that mediates a range of metabolic effects by using a transduction pathway from the long form of the leptin receptor, OB-R(L,) through Janus kinase-signal transducer and activator of transcription (Jak-Stat) signaling components. Leptin is produced by hepatic stellate cells (HSCs) but only following their "activation." Because activation of stellate cells is a central event in the fibrotic response to liver injury, we hypothesized that leptin may directly stimulate fibrogenesis in activated stellate cells via OB-R(L). We analyzed leptin receptors and their signaling partners in a stellate cell line (HSC-T6) as well as in primary stellate cell isolates. We also examined the effect of leptin on stellate cell expression of alpha(2)(I) collagen messenger RNA (mRNA) levels by ribonuclease protection analysis (RPA). Finally, we examined the role of leptin in in vivo fibrogenesis by inducing a wounding response in ob/ob mice, which lack functional leptin. HSC-T6 and culture-activated stellate cells expressed OB-R(L). Scatchard analysis verified specific binding of leptin to HSCs, with an association constant (K(d)) equal to 660 +/- 5.8 pmol/L. Exposure of HSCs to leptin resulted in significant increases in alpha(2)(I) collagen mRNA expression. Transient transfection with a promoter reporter construct showed a 3-fold increase in alpha(2)(I) collagen transgene activity. Leptin stimulated activation of Stat3 in activated HSCs. Finally, lean animals, but not ob/ob littermates, had significant fibrosis as assessed by picrosirius red staining and abundant alpha-smooth muscle actin staining. In conclusion, these results indicate that leptin is profibrogenic in activated HSCs and can signal via the Jak-Stat pathway. Up-regulation of leptin signaling in liver injury could contribute to enhanced fibrogenesis, particularly in states in which leptin levels are high.

Topics: Actins; Animals; Carrier Proteins; Cell Line, Transformed; Collagen; Collagen Type I; DNA-Binding Proteins; Gene Expression Regulation; Leptin; Liver; Liver Cirrhosis; Muscle, Smooth; Obesity; Rats; Receptors, Cell Surface; Receptors, Leptin; Reference Values; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Thinness; Trans-Activators; Transgenes

In this study, we investigated hepatic fibrogenesis caused by long-term thioacetamide (TAA) administration in ob/ob mice, a naturally occurring leptin deficient animal. In the lean littermates, prominent hepatic fibrosis, as well as positive staining for alpha smooth muscle actin (alpha-SMA), was induced by treatment with TAA (200 microg/g, IP, 3 times per week) for 4 to 8 weeks as expected. In sharp contrast, almost no hepatic fibrosis developed in ob/ob mice given the equivalent doses of TAA, where specific staining for alpha-SMA barely was detected. Induction of alpha1(I) procollagen mRNA caused by TAA also was prevented in ob/ob mice almost completely. Further, transforming growth factor beta (TGF-beta) mRNA was increased in the liver after TAA treatment for 4 weeks in lean littermates, which also was prevented in ob/ob mice. Interestingly, fibrotic septa in the hepatic lobules, as well as increases in alpha1(I) procollagen mRNA, was observed in ob/ob mice, when they were injected with recombinant murine leptin (1 microg/g daily) in combination with TAA treatment. Leptin per se did not cause any fibrotic changes in the liver in ob/ob mice. These findings clearly indicated that leptin deficiency is responsible for the resistance to TAA-induced profibrogenic responses in ob/ob mice. In conclusion, leptin appears to promote profibrogenic responses in the liver, in part, by up-regulation of TGF-beta.

Topics: Actins; Animals; Cells, Cultured; Female; Gene Expression; Immunohistochemistry; Leptin; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Procollagen; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thioacetamide; Transforming Growth Factor beta

Topics: Animals; Carrier Proteins; Leptin; Liver Cirrhosis; Mice; Mice, Obese; Obesity; Receptors, Cell Surface; Receptors, Leptin

Lines of evidence suggested a possible link between leptin and hepatic fibrosis; however, whether leptin modulates the fibrogenesis in the liver remains unclear. The purpose of this study, therefore, was to evaluate the effect of leptin on inflammatory and profibrogenic responses in the liver caused by hepatotoxic chemicals. Male C57Bl/6 mice were given carbon tetrachloride (CCl(4)) (0.1 microL/g body weight [BW], intraperitoneally [IP]) and/or recombinant murine leptin (1 microg/g BW, IP) simultaneously, and sacrificed up to 72 hours later. Further, some mice were given thioacetamide (TAA; 200 microg/g BW, IP) and leptin 3 times per week for 4 weeks to evaluate the effect of leptin on chronic fibrogenic responses. A simultaneous injection of leptin enhanced acute CCl(4)-induced necroinflammatory and subsequent fibrotic changes in the hepatic lobules. The steady-state messenger RNA (mRNA) levels of alpha1(I) procollagen and heat shock protein 47 (HSP47) in the liver were potentiated when leptin was injected together with CCl(4). Expression of alpha smooth muscle actin (alpha-SMA) in the liver after CCl(4) treatment was also augmented markedly in combination with leptin. Further, leptin increased transforming growth factor beta1 (TGF-beta1) mRNA in the liver 24 hours after acute CCl(4) about 4-fold higher than CCl(4) alone. Moreover, leptin enhanced hepatic fibrosis and induction of alpha1(I) procollagen mRNA caused by chronic TAA administration. Collectively, these findings indicated that leptin augments both inflammatory and profibrogenic responses in the liver caused by hepatotoxic chemicals. It is postulated that the increase in systemic leptin levels enhances up-regulation of TGF-beta1, leading to activation of stellate cells, thereby augmenting the fibrogenic response in the liver.

Topics: Actins; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Endotoxins; Heat-Shock Proteins; HSP47 Heat-Shock Proteins; Leptin; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth; Portal System; Procollagen; RNA, Messenger; Thioacetamide; Transaminases; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The pathophysiology of osteoporosis complicating chronic liver disease is unknown. Recent animal studies have found leptin to be a potent inhibitor of bone formation. The aim of this study was to investigate the relationship between serum leptin levels and bone mineral density in patients with chronic liver disease.. Fifty-eight patients, 39 females and 19 males, and age- and gender-matched controls were included. Bone mineral density was measured by using dual energy X-ray absorptiometry. Serum leptin was measured by using a radioimmunoassay.. The mean serum leptin concentration was 10.4 +/- 11.3 and 15.2 +/- 17.9 ng/mL; P=0.11, in the patients and controls, respectively. Leptin correlated positively with body mass index in patients (r=0.40; P=0.003) and in controls (r=0.55; P < 0.0001). In patients classified as Child-Pugh grade B and C, serum leptin correlated negatively with bone mineral density in females at both the lumbar spine and the femoral neck (r=-0.78; P=0.04 and r=-0.86; P=0.03, respectively). In male patients, the correlation was only significant at the lumbar spine (r=-0.99; P=0.002 and r=-0.86; P=0.06, at the lumbar spine and femoral neck, respectively). No correlation was found between serum leptin and bone mineral density in the controls.. An inverse relationship between serum leptin and bone mineral density was found in patients with advanced chronic liver disease. The reasons for these findings are uncertain, but a pathophysiological role of circulating leptin in osteoporosis in chronic liver disease is possible.

Topics: Absorptiometry, Photon; Adult; Aged; Body Mass Index; Bone Density; Case-Control Studies; Chronic Disease; Cohort Studies; Female; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Osteoporosis

In 18 patients with chronic hepatitis C we evaluated leptin (with IRMA method) and HGF and neopterin (with ELISA method) serum concentrations. Concentrations of leptin, HGF and neopterin were higher than in the control group. Leptin serum concentrations correlated with liver biopsy inflammatory grading, but higher HGF concentrations were connected with fibrosis staging. Neopterin correlated with both parameters and GGTP activity.. increased neopterin concentrations could inform about liver inflammation activity; leptin and HGF serum concentrations could reflect the liver damage intensity.

Topics: Adult; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Hepatitis C, Chronic; Hepatocyte Growth Factor; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Neopterin

Serum levels of leptin, the adipocyte-derived hormone regulating food intake and energy expenditure in mammals, have been found to be increased in cirrhotic patients. The aim of the present study was to investigate leptin serum level in relation to anthropometric features and liver function in patients with viral chronic hepatitis or liver cirrhosis.. Serum leptin levels were determined by radioimmunoassay in 30 male and 10 female patients with chronic hepatitis, in 42 male and 10 female patients with liver cirrhosis, and in four respective control groups. Liver function was evaluated by the monoethylglycinexylidide formation test. Body mass index and body fat mass were estimated by weight, height and skinfold thickness measurements.. Compared with controls, absolute serum leptin levels were significantly (p<0.01) lower in chronic hepatitis patients and similar in cirrhotic patients. Leptin serum levels were significantly (p<0.05) higher in cirrhotic than in chronic hepatitis patients. When expressed in relation to body fat mass, the above differences persisted; however, cirrhotic females showed significantly (p<0.05) higher serum leptin values than controls. Serum leptin values correlated negatively (p<0.01) with monoethylglycinexylidide serum values in all groups of patients.. In patients with chronic viral liver disease, serum leptin levels tend to increase as liver function worsens. This may reflect a decline in the ability to downregulate energy expenditure as an adaptation to anorexia and/or to defective substrate utilisation due to liver disease and may negatively influence body weight homeostasis in these patients.

Topics: Adipose Tissue; Adult; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Leptin; Lidocaine; Liver Cirrhosis; Male; Middle Aged; Organ Size; Reference Values

Little information is available on the involvement of leptin in clinical conditions associated with malnutrition, such as liver cirrhosis. The behaviour of serum leptin in patients with different Child-Pugh score, post-hepatitis liver cirrhosis and insulin sensitivity has therefore been investigated and compared with that in alcoholic Child C patients.. Sixty-four patients, aged 51 to 62 years, with different degrees of post-hepatitis cirrhosis or Child C alcoholic cirrhosis were compared with 15 age-matched control subjects. Body composition was estimated by skinfold thickness. Serum leptin, glucose and insulin were assayed.. In post-hepatitis patients a significant reduction in leptin levels was observed as the Child-Pugh score worsened (men: 2.94+/-1.61 in Child C vs 6.78+/-2.49 ng/ml in controls, p<0.001; women: 4.14+/-0.66 in Child C vs 16.16+/-3.90 ng/ml in controls, p<0.02). Conversely, only the men with alcoholic liver cirrhosis showed a significant difference in leptin concentration compared to controls (8.5+/-2.1 vs 16.4+/-7.9 kg, p<0.05). In particular, Child C, alcoholic cirrhotic women had a significantly (p=0.03) higher level of leptin than post-hepatitis matched women. A positive correlation was observed between leptin and fat mass (men R2=0.59, p<0.0001 and women R2=0.65, p<0.0001). While fasting levels of serum leptin correlated significantly with insulin concentrations in controls, a similar relationship was not observed in the cirrhotic population, which displayed higher insulin concentrations than controls.. In contrast to findings in alcoholic cirrhotic women, low leptin values in post-hepatitis cirrhotic patients mainly represent the expression of a reduced fat mass.

Topics: Adipose Tissue; Fasting; Female; Hepatitis B; Hepatitis C; Humans; Insulin Resistance; Leptin; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Organ Size; Reference Values

The presence of steatosis is a common histological finding in patients with chronic hepatitis C (CHC). The causes of the severity of this condition are not yet clear, although both metabolic and viral factors supposedly are involved. In this study our aim was to examine the possible influence that leptin levels, hepatitis C virus (HCV) RNA levels, and hepatitis G virus (HGV) infection have on the severity of steatosis and on the presence and degree of fibrosis in patients with CHC.. One hundred eighty-two CHC patients with histological findings of steatosis were chosen from among a cohort of patients referred to our center for staging of liver disease. Among them 48 CHC patients were accurately selected so as to rule out possible confounding factors for the presence of steatosis (diabetes mellitus, hyperlipemia, obesity, alcohol). Leptin levels, HCV RNA levels, and HCV genotype, and the presence of HGV RNA were assessed in these patients and related to histological findings.. We found that leptin levels in CHC patients were similar to those in healthy subjects. No relationship was found between leptin levels and severity of steatosis. HCV RNA levels, HCV genotype, and the presence of HGV infection were no different among CHC patients with various degrees of steatosis. Leptin was not related to different degrees of fibrosis, whereas higher viral load was the only parameter associated to higher fibrosis scores.. These findings suggest that the degree of steatosis in patients with CHC does not seem to depend on serum leptin levels or on viral factors, at least as far as HCV viremia and genotype and HGV infection are concerned. The severity of fibrosis does not seem to be influenced by leptin levels, whereas HCV viral load does seem to play some role.

Topics: Adult; Case-Control Studies; Fatty Liver; Female; Flaviviridae; Hepacivirus; Hepatitis C, Chronic; Hepatitis, Viral, Human; Humans; Leptin; Liver; Liver Cirrhosis; Male; Middle Aged; RNA, Viral; Severity of Illness Index; Viral Load

Leptin, found to be elevated in patients with liver cirrhosis, may contribute to the inadequate energy expenditure and malnutrition associated with a negative prognosis for these patients. Our aim was to characterize leptin components and their relationships to body composition, resting energy expenditure (REE), and substrate use in patients with posthepatic liver cirrhosis.. Using specific radioimmunoassays, we measured free leptin and bound leptin in 27 cirrhotics and 27 matched control subjects. In the cirrhotic group, body composition and REE were determined.. Free leptin was not different in cirrhotics and control subjects and was related to body mass index (controls: r = 0.34, P < 0.05; cirrhotics: r = 0.55, P < 0.005) and to fat mass (cirrhotics: r = 0.76, P < 0.0001). Bound leptin was significantly higher in cirrhotic subjects than in controls (P < 0.001) and was related to REE x fat-free mass(-1) (r = 0.57, P < 0.005) or to the difference between measured and estimated REE (r = 0.55, P < 0.005).. Free leptin reflects fat mass in controls and cirrhotics. Increased serum leptin in cirrhotics is a result of increased bound leptin serum concentrations, which are positively related to energy expenditure. Moreover, bound leptin may be a useful marker for inadequate energy expenditure in patients with liver cirrhosis.

Topics: Adipose Tissue; Body Composition; Body Mass Index; Energy Metabolism; Female; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Reference Values; Rest

Leptin, the ob gene product, is an anorexigenic peptide secreted from adipose tissue. However, the mechanism of leptin clearance/degradation has not been well determined in humans. The present study was undertaken to examine a possible involvement of liver in determining circulating leptin concentrations in humans.. In the present study 58 healthy control subjects and 68 patients with liver cirrhosis (LC) without any renal dysfunction were randomly included.. The serum immunoreactive leptin (IRL) concentrations relative to the body mass index (BMI) were determined. Serum IRL and estradiol (E2) concentrations were assayed by radioimmunoassay (RIA).. The correlations between the BMI and circulating IRL concentrations were all significant in male healthy controls (M-C), male patients with LC (M-LC), female healthy controls (F-C) and female patients with LC (F-LC). Circulating IRL concentrations were significantly higher than control in F-LC but not M-LC groups. The ratio of circulating IRL concentrations to the BMI was significantly higher in the M-LC group than in the M-C group and also significantly higher in the F-LC group than in the F-C group. The correlation between the IRL/BMI ratio and serum total bilirubin concentrations was significant (r = 0.417, P < 0.05) in the M-LC group, but not in the F-LC group. There was no significant correlation of the IRL/BMI ratio to serum E2 or albumin concentrations in either M-LC or F-LC groups.. The present data demonstrated that the rate of increase in circulating IRL concentrations with the BMI was higher in LC patients of both genders. Liver may play a role in determining circulating leptin levels.

Topics: Aged; Bilirubin; Body Mass Index; Estradiol; Female; Humans; Leptin; Liver Cirrhosis; Male; Middle Aged; Proteins; Serum Albumin