endothelin-1 and Non-alcoholic-Fatty-Liver-Disease

This study investigated the impact of exercise training on major pulmonary vasomotor mediators and receptors including endothelial nitric oxide synthase (eNOS) inducible NOS (iNOS), endothelin-1 (ET-1), ET-1 receptors A (ET

Topics: Endothelin-1; Exercise; Humans; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Non-alcoholic Fatty Liver Disease; Receptor, Endothelin A; RNA, Messenger

We aim to evaluate the effects of auranofin, a known antioxidant, on hepatic steatosis, inflammation, and fibrosis, contributing to non-alcoholic steatohepatitis (NASH) development in vivo and in vitro.. Transcriptome analysis of LX-2 cells was that expression patterns of genes changed by auranofin, and their related pathways were estimated. We used the gene set enrichment analysis (GSEA) program to determine the pathway involved in overall genetic change. In vitro, LX-2 and HepG2 cells were treated with transforming growth factor (TGF)-β1 and palmitic acid (PA), respectively, and the antifibrotic and antiadipogenic effect function of auranofin was evaluated.. Transcriptome analysis revealed that auranofin decreased the expression of 15 genes, including thrombospondin 1, endothelin 1 (ET-1), fibronectin 1, and LOX. The molecular functions of these genes are involved in collagen binding. GSEA of the overall gene expression pattern revealed that many genes increased in the reactive oxygen species pathway and decreased in the inflammatory response. Auranofin decreased nuclear factor kappa B (NF-κB) and IκBα in TGF-β1-induced LX-2 cells, thereby reducing ET-1 and fibrosis. Furthermore, increased pNRF2 in PA-induced HepG2 cells led to increased antioxidant marker expression and decreased lipid accumulation. In the bile duct ligation model mice, auranofin reduced the fibrosis area and increased the survival rate. Auranofin reduced liver fibrosis and lipid accumulation in NASH model mice fed on a Western diet.. Auranofin inhibits lipogenesis and fibrosis formation and is a proposed candidate for NASH treatment.

Topics: Animals; Antioxidants; Auranofin; Collagen; Endothelin-1; Fibronectins; Humans; Liver; Liver Cirrhosis; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; NF-kappa B; NF-KappaB Inhibitor alpha; Non-alcoholic Fatty Liver Disease; Palmitic Acid; Reactive Oxygen Species; Signal Transduction; Thrombospondin 1; Transforming Growth Factor beta1; Transforming Growth Factors

Fibrotic processes in the liver of non-alcoholic steatohepatitis (NASH) patients cause microcirculatory dysfunction in the organ which increases blood vessel resistance and causes portal hypertension. Assessing blood vessel function in the liver is challenging, necessitating the development of novel methods in normal and fibrotic tissue that allow for drug screening and translation toward pre-clinical settings. Cultures of precision cut liver slices (PCLS) from normal and fibrotic rat livers were used for blood vessel function analysis. Live recording of vessel diameter was used to assess the response to endothelin-1, serotonin and soluble guanylate cyclase (sGC) activation. A cascade of contraction and relaxation events in response to serotonin, endothelin-1, Ketanserin and sGC activity could be established using vessel diameter analysis of rat PCLS. Both the sGC activator BI 703704 and the sGC stimulator Riociguat prevented serotonin-induced contraction in PCLS from naive rats. By contrast, PCLS cultures from the rat CCl

Topics: Adenosine Triphosphate; Animals; Blood Vessels; Carbon Tetrachloride; Endothelin-1; Ketanserin; Liver; Liver Cirrhosis; Male; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Pyrazoles; Pyrimidines; Rats, Sprague-Dawley; Rats, Wistar; Serotonin; Signal Transduction; Soluble Guanylyl Cyclase; Vasoconstriction; Vasodilation

In non-alcoholic steatohepatitis (NASH), decreased nitric oxide and increased endothelin-1 (ET-1, also known as EDN1) released by sinusoidal endothelial cells (LSEC) induce hepatic stellate cell (HSC) contraction and contribute to portal hypertension (PH). Statins improve LSEC function, and ambrisentan is a selective endothelin-receptor-A antagonist. We aimed to analyse the combined effects of atorvastatin and ambrisentan on liver histopathology and hemodynamics, together with assessing the underlying mechanism in a rat NASH model. Diet-induced NASH rats were treated with atorvastatin (10 mg/kg/day), ambrisentan (30 mg/kg/day or 2 mg/kg/day) or a combination of both for 2 weeks. Hemodynamic parameters were registered and liver histology and serum biochemical determinations analysed. Expression of proteins were studied by immunoblotting. Conditioned media experiments were performed with LSEC. HSCs were characterized by RT-PCR, and a collagen lattice contraction assay was performed. Atorvastatin and ambrisentan act synergistically in combination to completely normalize liver hemodynamics and reverse histological NASH by 75%. Atorvastatin reversed the sinusoidal contractile phenotype, thus improving endothelial function, whereas ambrisentan prevented the contractile response in HSCs by blocking ET-1 response. Additionally, ambrisentan also increased eNOS (also known as Nos3) phosphorylation levels in LSEC, via facilitating the stimulation of endothelin-receptor-B in these cells. Furthermore, the serum alanine aminotransferase of the combined treatment group decreased to normal levels, and this group exhibited a restoration of the HSC quiescent phenotype. The combination of atorvastatin and ambrisentan remarkably improves liver histology and PH in a diet-induced NASH model. By recovering LSEC function, together with inhibiting the activation and contraction of HSC, this combined treatment may be an effective treatment for NASH patients.

Topics: Alanine Transaminase; Animals; Atorvastatin; Biomarkers; Collagen; Disease Models, Animal; Drug Synergism; Endothelial Cells; Endothelin-1; Enzyme Activation; Hemodynamics; Hepatic Stellate Cells; Insulin Resistance; Liver; Liver Cirrhosis; Nitric Oxide Synthase Type III; Non-alcoholic Fatty Liver Disease; Phenylpropionates; Pyridazines; Weight Gain

Activation of the vascular endothelin-1 (ET-1) system is a key abnormality in vascular dysfunction of human obesity, especially in patients developing complications, such as the metabolic syndrome, diabetes, and atherosclerosis. Vascular insulin resistance, an increased insulin-stimulated endothelial production of ET-1 combined with impaired nitric oxide availability, is the hallmark of obesity-related vasculopathy, but dysregulated adipokine release from obese adipose tissue may contribute to the predominance of ET-1-dependent vasoconstriction. ET-1, in turn, might determine unhealthy obese adipose tissue expansion, with visceral and perivascular adipose tissue changes driving the release of inflammatory cytokines and atherogenic chemokines. In addition, ET-1 might also play a role in the development of the metabolic complications of obesity. Studies have shown inhibition of lipoprotein lipase activity by ET-1, with consequent hypertriglyceridemia. Also, ET-1 in pancreatic islets seems to contribute to beta cell dysfunction, hence affecting insulin production and development of diabetes. Moreover, ET-1 may play a role in nonalcoholic steatohepatitis. Recent clinical trials using innovative design have demonstrated that antagonism of ET-type A receptors protects against some complications of obesity and diabetes, such as nephropathy. These findings encourage further investigation to evaluate whether targeting the ET-1 system could afford better protection against other consequences of the obesity epidemic.

Topics: Adipokines; Adipose Tissue; Cytokines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Non-alcoholic Fatty Liver Disease; Obesity; Receptor, Endothelin A; Vasoconstriction

Introduction: The study increase in the incidence of non-alcoholic steatohepatitis (NASH) on the background of obesity and chronic kidney disease (CKD) in people of working age in Ukraine and in the world necessitates the research into mechanisms of mutual burden and the search for new factors in the pathogenesis of this comorbidity progression . The aim: To establish the role of endothelial dysfunction in the mechanisms of mutual burden and progression of non-alcoholic steatohepatitis and chronic kidney disease in patients with obesity.. Materials and methods: 135 patients were examined: of which 52 patients with non-alcoholic steatohepatitis with obesity I degree (1 group), 53 patients with nonalcoholic steatohepatitis with comorbid obesity of the I degree and chronic kidney disease of the І-ІІ stage (group 2). The control group consisted of 30 practically healthy persons of the corresponding age and sex. The average age of patients was (45.8 ± 3.81) years.. Results: The results of the study showed that in patients with NASH, a significant increase in the content of NO in the blood was detected in comparison with the index in PHP (p <0,05) in group 1 - in 2,1 times, in the 2nd group - in 2,6 times (p <0,05). The role of nitrosative stress in the pathogenesis of NASH was proved, the confirmation of which is the increase in the concentration of nitrosothiols, peroxynitrite and other metabolites NO in the blood. Increased peroxynitrite formation due to the generation of NO by leukocytes is an important aspect of the damaging effect and inflammation process in NASH. Pathological hyperproduction of NO by endothelial cells and leukocytes from inflammatory infiltrates in the liver contributes to the development of nitrosative stress in NASH. The established hypernitrate in blood may also be considered compensatory in response to hyperproduction of ET-1 in all observational groups.. Conclusions: Confirmation of the presence of endothelial dysfunction (ED) in patients with NASH with CKD resulted in a probable growth of the number of desquamated endothelial cells (DEC) in the 2nd group of patients in 1.9 times (p2 <0.05). Generation by neutrophils during the exacerbation of NASH of a significant number of active forms of oxygen and nitrogen and hyperproduction of endothelial cells and endometrial lymphocytes with progressive damage to the endothelium (growth of DEC) leads to significant ED, accompanied by mosaic angiospasm of the arteries due to hyperproduction of ET-1 and parectic vasodilatation of the veins of the portal vein system because of the hyperproduction of NO.

Topics: Adult; Case-Control Studies; Disease Progression; Endothelin-1; Endothelium, Vascular; Humans; Middle Aged; Nitric Oxide; Non-alcoholic Fatty Liver Disease; Obesity; Renal Insufficiency, Chronic; Ukraine

To study the relationship between non-alcoholic steatohepatitis (NASH) and atherosclerosis in young and middle-aged patients, and to provide clinical evidence that will aid in prevention and prediction of development of atherosclerosis or cardiovascular diseases in patients with non-alcoholic fatty liver disease (NAFLD).. Fifty-one patients with biopsy-proven NAFLD (18 to 60 years in age) were divided into two groups: cases with simple non-alcoholic fatty liver (NAFL, n = 11) and cases with NASH (n = 40). All subjects underwent physical examination and anthropometric measurements. Fasting serum was assayed by blood biochemistry. Insulin resistance was estimated by the homeostatic model assessment index (HOMA-IR). Serum levels of high-sensitivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and endothelin-1 (ET-1) were detected by enzyme-linked immunosorbent assay. Carotid intima-media thickness (CIMT) was estimated by carotid ultrasound. Brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index were estimated using a volume-plethysmographic apparatus. Data for the two groups were summarized as mean +/- SD or interquartile range and intergroup differences were evaluated by paired t-test or Wilcoxon test, with two-sided P-values less than 0.05 indicating significance.. The serum levels of hs-CRP, sICAM-1, and ET-1 were significantly higher in the NASH group than the NAFL group (all P less than 0.001). In addition, the CIMT and baPWV were significantly higher in the NASH group than the NAFL group (both P less than 0.05). The HOMA-IR was also significantly higher in the NASH group than the NAFL group (P less than 0.001).. Liver inflammation and insulin resistance may play important, and possibly collaborative, roles in promoting arterial endothelial dysfunction and atherosclerosis in NAFLD patients. NASH patients, especially those who are young and middle-aged, may benefit from early monitoring and prevention strategies to help decrease the risk of developing severe cardiovascular diseases.

Topics: Adolescent; Adult; Atherosclerosis; C-Reactive Protein; Carotid Arteries; Carotid Intima-Media Thickness; Endothelin-1; Female; Humans; Insulin; Insulin Resistance; Intercellular Adhesion Molecule-1; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Young Adult

Leptin, the ob gene product, is a protein released from adipocytes and has been detected in fibrotic and cirrhotic livers. Leptin in brain has an inhibitory effect on food intake. Nonalcoholic steatohepatitis (NASH) is characterized by hyperleptinemia. This study explores the possible mechanisms of hyperleptinemia in relation to increased intrahepatic resistance (IHR) and portal hypertension in NASH cirrhotic rats. NASH cirrhotic rats with hyperleptinemia were induced in Zucker (fa/fa) and lean rats by feeding the animals a high fat/methionine-choline-deficient (HF/MCD) diet with and without exogenous administration of recombinant leptin. Portal venous pressure (PVP), IHR, plasma and hepatic levels of various substances, histopathology of the liver, the hepatic hydroxyproline content, and the expression of various hepatic protein and messenger RNA (mRNA) were measured. Hepatic microcirculatory dysfunction and the vasoconstrictive response to endothelin-1 were also observed using a liver perfusion system and intravital microscopy. Finally, the effect of leptin on hepatic stellate cells (HSCs) was evaluated. Both in HF/MCD-Zucker and HF/MCD+leptin lean rats, significant hepatic fibrogenesis and cirrhosis, marked portal hypertension, microcirculatory dysfunction, an enhanced vasoconstrictive response to endothelin-1, and an increased IHR were found to be associated with higher levels of hepatic endothelin-1 and endocannabinoids, expression levels of the cannabinoid type 1 receptor, endothelin-1 type A receptor (ET(A) R), activator protein-1, transforming growth factor beta (TGF-β)(1), osteopontin, tumor necrosis factor alpha (TNF-α), leptin, and the leptin receptor (OBRb). Interestingly, acute incubation of leptin directly increases the expression of ET(A) R, OBRb and activator protein-1 in HSCs.. An HF/MCD diet and hyperleptinemia increase hepatic endocannabinoids production, promote hepatic fibrogenesis, enhance the hepatic vasoconstrictive response to endothelin-1, and aggravate hepatic microcirculatory dysfunction; these events subsequently increase IHR and portal hypertension in NASH cirrhotic rats.

Topics: Animals; Biopsy, Needle; Body Weight; Cannabinoid Receptor Modulators; Diet, High-Fat; Disease Models, Animal; Disease Progression; Endocannabinoids; Endothelin-1; Fatty Liver; Hepatic Stellate Cells; Hypertension, Portal; Immunohistochemistry; Insulin Resistance; Kupffer Cells; Leptin; Liver; Microcirculation; Non-alcoholic Fatty Liver Disease; Random Allocation; Rats; Rats, Zucker; RNA, Messenger; Statistics, Nonparametric