obeticholic-acid and Inflammation

Fatty acids beyond their role as an endogenous energy source and storage are increasingly considered as signaling molecules regulating various physiological effects in metabolism and inflammation. Accordingly, the molecular targets involved in formation and physiological activities of fatty acids hold significant therapeutic potential. A number of these fatty acid targets are addressed by some of the oldest and most widely used drugs such as cyclooxygenase inhibiting NSAIDs, whereas others remain unexploited. Compounds orthosterically binding to proteins that endogenously bind fatty acids are considered as fatty acid mimetics. On the basis of their structural resemblance, fatty acid mimetics constitute a family of bioactive compounds showing specific binding thermodynamics and following similar pharmacokinetic mechanisms. This perspective systematically evaluates targets for fatty acid mimetics, investigates their common structural characteristics, and highlights demands in their discovery and design. In summary, fatty acid mimetics share particularly favorable characteristics justifying the conclusion that their therapeutic potential vastly outweighs the challenges in their design.

Topics: Animals; Cyclooxygenase Inhibitors; Drug Discovery; Fatty Acids; Humans; Inflammation; Models, Molecular

Bile acids act as steroid hormones, controlling lipid, glucose and energy metabolism, as well as inflammation and fibrosis. Their actions are implemented through activation of nuclear (FXR, VDR, PXR) and membrane G protein-coupled (TGR5, S1PR2) receptors. Areas covered: This review discusses the potential of FXR and TGR5 as therapeutic targets in the treatment of pulmonary disorders linked to metabolism and/or inflammation. Obeticholic acid (OCA) is the most clinically advanced bile acid-derived agonist for FXR-mediated anti-inflammatory and anti-fibrotic effects. It therefore represents an attractive pharmacological approach for the treatment of lung conditions characterized by vascular and endothelial dysfunctions. Expert opinion: Inflammation, vascular remodeling and fibrotic processes characterize the progression of pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF). These processes are only partially targeted by the available therapeutic options and still represent a relevant medical need. The results hereby summarized demonstrate OCA efficacy in preventing experimental lung disorders, i.e. monocrotaline-induced PAH and bleomycin-induced fibrosis, by abating proinflammatory and vascular remodeling progression. TGR5 is also expressed in the lung, and targeting the TGR5 pathway, using the TGR5 agonist INT-777 or the dual FXR/TGR5 agonist INT-767, could also contribute to the treatment of pulmonary disorders mediated by inflammation and fibrosis.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Drug Design; Humans; Inflammation; Lung Diseases; Molecular Targeted Therapy; Pulmonary Fibrosis; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled

Farnesoid X receptor (FXR) agonist obeticholic acid (OCA) has emerged as a potential therapy for nonalcoholic fatty liver disease (NAFLD). However, the side effects of OCA may limit its application in clinics. We identified previously that isotschimgine (ITG) is a non-steroidal FXR selective agonist and has potent therapeutic effects on NAFLD in mice. Here, we aimed to evaluate the therapeutic effects of ITG on nonalcoholic steatohepatitis (NASH) and fibrosis in mice. We used methionine and choline deficient (MCD) diet-induced NASH mice, bile duct ligation (BDL), and carbon tetrachloride (CCl

Topics: Animals; Carbon Tetrachloride; Chenodeoxycholic Acid; Diet; Inflammation; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Phenyl Ethers

Nonalcoholic steatohepatitis (NASH) is a chronic progressive disease with complex pathogenesis of which the bile acids (BAs) and gut microbiota are involved. Soyasaponins (SS) exhibits many health-promoting effects including hepatoprotection, but its prevention against NASH is unclear. This study aims to investigate the preventive bioactivities of SS monomer (SS-A. The methionine and choline deficient (MCD) diet-fed male C57BL/6 mice were intervened with obeticholic acid or SS-A. SS-A

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Choline Deficiency; Colon; Diet; Disease Models, Animal; Gastrointestinal Microbiome; Inflammation; Liver; Male; Methionine; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Saponins

The role of n-3 polyunsaturated fatty acids (PUFAs) in alcoholic liver disease (ALD) has been controversial. N-3 PUFA oxidation in animal feeding stuffs was rarely concerned, likely contributing to inconsistent outcomes. Here, we report the impacts of oxidized fish oil (OFO) on ALD in C57BL/6 mice. Alcohol exposure increased plasma aminotransferase levels and hepatic inflammation. These deleterious effects were ameliorated by unoxidized FO but exacerbated by OFO. Sequencing analysis showed the accentuated intestinal dysbiosis and the increased proportion of Proteobacteria in OFO-fed mice. Intestinal sterilization by antibiotics completely abolished OFO-aggravated liver injury. Additionally, alcohol exposure leads to the greater increase in plasma endotoxin and decrease in intestinal tight junction protein expressions in OFO-fed mice. Stabilization of intestinal barrier by obeticholic acid markedly blunted OFO-aggravated liver injury in alcohol-fed mice. These results demonstrate that OFO exacerbates alcoholic liver injury through enhancing intestinal dysbiosis, barrier dysfunction, and hepatic inflammation mediated by gut-derived endotoxin.

Topics: Animals; Anti-Bacterial Agents; Chenodeoxycholic Acid; Dysbiosis; Ethanol; Fish Oils; Gastrointestinal Microbiome; Inflammation; Intestines; Liver; Liver Diseases, Alcoholic; Mice; Oxidation-Reduction; RNA, Ribosomal, 16S

Fatty liver disease, including non-alcoholic fatty liver (NAFLD) and steatohepatitis (NASH), has been associated with increased intestinal barrier permeability and translocation of bacteria or bacterial products into the blood circulation. In this study, we aimed to unravel the role of both intestinal barrier integrity and microbiota in NAFLD/NASH development.. C57BL/6J mice were fed with high-fat diet (HFD) or methionine-choline-deficient diet for 1 week or longer to recapitulate aspects of NASH (steatosis, inflammation, insulin resistance). Genetic and pharmacological strategies were then used to modulate intestinal barrier integrity.. We show that disruption of the intestinal epithelial barrier and gut vascular barrier (GVB) are early events in NASH pathogenesis. Mice fed HFD for only 1 week undergo a diet-induced dysbiosis that drives GVB damage and bacterial translocation into the liver. Fecal microbiota transplantation from HFD-fed mice into specific pathogen-free recipients induces GVB damage and epididymal adipose tissue enlargement. GVB disruption depends on interference with the WNT/β-catenin signaling pathway, as shown by genetic intervention driving β-catenin activation only in endothelial cells, preventing GVB disruption and NASH development. The bile acid analogue and farnesoid X receptor agonist obeticholic acid (OCA) drives β-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects against GVB disruption, both as a preventive and therapeutic agent. Importantly, we found upregulation of the GVB leakage marker in the colon of patients with NASH.. We have identified a new player in NASH development, the GVB, whose damage leads to bacteria or bacterial product translocation into the blood circulation. Treatment aimed at restoring β-catenin activation in endothelial cells, such as administration of OCA, protects against GVB damage and NASH development.. The incidence of fatty liver disease is reaching epidemic levels in the USA, with more than 30% of adults having NAFLD (non-alcoholic fatty liver disease), which can progress to more severe non-alcoholic steatohepatitis (NASH). Herein, we show that disruption of the intestinal epithelial barrier and gut vascular barrier are early events in the development of NASH. We show that the drug obeticholic acid protects against barrier disruption and thereby prevents the development of NASH, providing further evidence for its use in the prevention or treatment of NASH.

Topics: Animals; Bacterial Translocation; Capillary Permeability; Chenodeoxycholic Acid; Diet, High-Fat; Disease Models, Animal; Dysbiosis; Gastrointestinal Microbiome; Inflammation; Insulin Resistance; Intestinal Mucosa; Liver; Mice; Non-alcoholic Fatty Liver Disease; Protective Agents

Intrahepatic cholestasis of pregnancy (ICP) is gestation-specific liver disease associated with liver injury and increased serum and hepatic bile acids. Although the mechanism of ICP is still not fully understood, the reproductive hormones seem to play an important role. Recent studies show that a progesterone metabolite, epiallopregnanolone sulfate (PM5S), is supraphysiologically elevated in the serum of ICP patients, indicating it may play an etiology role in ICP. Bile acid homeostasis is controlled by multiple mechanisms including farnesoid X receptor (FXR)-mediated bile acid export and synthesis. It is known that cholic acid (CA), a primary bile acid, can activate FXR, which is inhibited by PM5S, an FXR antagonist. Here we employed a mouse model of concurrent exposure of CA and PM5S-induced liver injury and determined the effects of probiotic Lactobacillus rhamnosus GG (LGG) in the prevention of the bile acid disorders and liver injury. Mice challenged with CA + PM5S had significantly increased levels of serum and hepatic bile acids and bilirubin and liver enzyme. Pretreatment with LGG significantly reduced bile acid and bilirubin levels associated with reduced liver enzyme level and mRNA expression levels of pro-inflammatory cytokines. We also showed that the beneficial effects of LGG is likely mediated by hepatic FXR activation and bile salt export pump (BSEP) upregulation. In conclusion, our results provide a rationale for the application of probiotics in the management of ICP through gut microbiota-mediated FXR activation.

Topics: Angiogenic Proteins; Animals; Bile Acids and Salts; Bilirubin; Chenodeoxycholic Acid; Cholestasis; Cholesterol 7-alpha-Hydroxylase; Cholic Acid; Cytokines; Disease Models, Animal; Gastrointestinal Microbiome; Inflammation; Lacticaseibacillus rhamnosus; Liver; Male; Mice; Mice, Inbred C57BL; Pregnanolone; Probiotics; RNA-Binding Proteins; Signal Transduction; Ursodeoxycholic Acid

Acute lung injury (ALI) is a common disease that may result in acute respiratory failure and death. However, there are still no effective treatments for ALI. Several studies have shown that farnesoid X receptor (FXR) has an anti-inflammatory effect. We investigated the effects of obeticholic acid (OCA), an agonist of FXR, on Lipopolysaccharide (LPS)-induced ALI in mice. Sixty male mice were randomly divided into six groups, and orally administered with or without OCA once daily for 3 consecutive days before LPS (1.0 mg/kg). Animals were sacrificed at 0 h, 2 h or 6 h after LPS. As expected, OCA enhanced pulmonary FXR activity. OCA prevented LPS-induced ALI. Additional experiment showed that OCA alleviated LPS-induced up-regulation of pulmonary pro-inflammatory and chemokine genes. Moreover, OCA also repressed LPS-induced the release of TNF-α and KC in serum and bronchoalveolar lavage fluid. In contrast, OCA further up-regulated LPS-induced the expression of Il-10, an anti-inflammatory cytokine. Further study showed that OCA inhibited LPS-evoked NF-κB signaling in the lungs. OCA attenuated LPS-induced ERK1/2, JNK, p38 and Akt phosphorylation in the lungs. Overall, these results suggest that OCA prevent LPS-induced ALI may be through enhancing pulmonary FXR activity and then blockading several inflammatory signaling pathways.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Chenodeoxycholic Acid; Disease Models, Animal; Humans; Inflammation; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; NF-kappa B; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Tumor Necrosis Factor-alpha

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that regulates genes involved in bile acid metabolism. Accumulating data demonstrate that FXR has an anti-inflammatory activity. The present study aimed to investigate the effect of obeticholic acid (OCA), a novel synthetic FXR agonist, on D-galactosamine (GalN)/lipopolysaccharide (LPS)-evoked acute liver injury. All mice except controls were intraperitoneally injected with GalN (300 mg/kg) plus LPS (2.5 μg/kg). Some mice were pretreated with OCA (10 mg/kg) 48, 24 and 1 h before GalN/LPS. As expected, pretreatment with OCA alleviated hepatocyte apoptosis at early and middle stages of GalN/LPS-induced acute liver failure. By contrast, pretreatment with OCA augmented hepatic injury and inflammatory cell infiltration at middle stage of GalN/LPS-induced acute liver failure. Additional experiment found that OCA inhibited hepatic NF-κB activation at early and middle stages of GalN/LPS-induced acute liver failure. Interestingly, OCA inhibited hepatic proinflammatory cytokine tnf-α and il-6 but upregulated hepatic anti-inflammatory cytokine il-10 at early stage of GalN/LPS-induced acute liver failure. By contrast, OCA suppressed hepatic anti-inflammatory cytokine tgf-β and il-10 at middle stage of GalN/LPS-induced acute liver injury. These results suggest that FXR agonist OCA differentially regulates hepatic injury and inflammation at different stages of GalN/LPS-evoked acute liver failure.

Topics: Animals; Cell Death; Chenodeoxycholic Acid; Female; Galactosamine; Gene Expression Regulation; Inflammation; Lipopolysaccharides; Liver; Liver Failure, Acute; Mice; NF-kappa B

microRNAs were recently suggested to contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a disease lacking specific pharmacological treatments. In that regard, nuclear receptors are arising as key molecular targets for the treatment of nonalcoholic steatohepatitis (NASH). Here we show that, in a typical model of NASH-associated liver damage, microRNA-21 (miR-21) ablation results in a progressive decrease in steatosis, inflammation and lipoapoptosis, with impairment of fibrosis. In a complementary fast food (FF) diet NASH model, mimicking features of the metabolic syndrome, miR-21 levels increase in both liver and muscle, concomitantly with decreased expression of peroxisome proliferator-activated receptor α (PPARα), a key miR-21 target. Strikingly, miR-21 knockout mice fed the FF diet supplemented with farnesoid X receptor (FXR) agonist obeticholic acid (OCA) display minimal steatosis, inflammation, oxidative stress and cholesterol accumulation. In addition, lipoprotein metabolism was restored, including decreased fatty acid uptake and polyunsaturation, and liver and muscle insulin sensitivity fully reinstated. Finally, the miR-21/PPARα axis was found amplified in liver and muscle biopsies, and in serum, of NAFLD patients, co-substantiating its role in the development of the metabolic syndrome. By unveiling that miR-21 abrogation, together with FXR activation by OCA, significantly improves whole body metabolic parameters in NASH, our results highlight the therapeutic potential of nuclear receptor multi-targeting therapies for NAFLD.

Topics: Animals; Apoptosis; Chenodeoxycholic Acid; Disease Models, Animal; Fast Foods; Inflammation; Liver Cirrhosis; Male; Mice; Mice, Knockout; MicroRNAs; Non-alcoholic Fatty Liver Disease; PPAR alpha; Receptors, Cytoplasmic and Nuclear

Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown.. The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice.. 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group. The serum and livers were collected for further analysis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBIL) were measured at indicated time after LPS administration. Liver sections were stained with hematoxylin & eosin (H&E). Orally OCA pretreatment stimulated the expression of FXR and BSEP in livers and protected mice from LPS-induced hepatocyte apoptosis and inflammatory infiltration. Consistently, LPS-induced higher serum levels of ALT, AST, TBA and TBIL were significantly reversed by OCA administration. Meanwhile, the mRNA levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 were decreased in livers of mice in LPS + OCA group compared with LPS group. Further investigation indicated that the higher expression of ATF4 and LC3II/I were associated with the protective effect of OCA on LPS-induced liver injury.. Orally OCA pretreatment protects mice from LPS-induced liver injury possibly contributed by improved bile acid homeostasis, decreased inflammatory factors and ATF4-mediated autophagy activity in hepatocytes.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Chenodeoxycholic Acid; Cholestasis; Hepatocytes; Inflammation; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Protective Agents; Receptors, Cytoplasmic and Nuclear

Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development and even induce fibrosis regression in liver, kidney and intestine in multiple disease models. OCA also inhibits liver fibrosis in nonalcoholic steatohepatitis patients. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the effects of OCA treatment (3, 10 or 30mg/kg, daily for 5days a week, for 7 and/or 28 days) on inflammation, tissue remodeling and fibrosis in the monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) rat model. Treatment with OCA attenuated MCT-induced increased pulmonary arterial wall thickness and right ventricular hypertrophy, by i) blunting pathogenic inflammatory mechanisms (downregulation of interleukin 6, IL-6, and monocyte chemoattractant protein-1, MCP-1) and ii) enhancing protective mechanisms counteracting fibrosis and endothelial/mesenchymal transition. MCT-injected rats also showed a marked decrease of pulmonary artery responsiveness to both endothelium-dependent and independent relaxant stimuli, such as acetylcholine and a nitric oxide donor, sodium nitroprusside. Administration of OCA (30mg/kg) normalized this decreased responsiveness. Accordingly, OCA treatment induced profound beneficial effects on lung histology. In particular, both OCA doses markedly reduced the MCT-induced medial wall thickness increase in small pulmonary arteries. To evaluate the objective functional improvement by OCA treatment of MCT-induced PAH, we performed a treadmill test and measured duration of exercise. MCT significantly reduced, and OCA normalized treadmill endurance. Results with OCA were similar, or even superior, to those obtained with tadalafil, a well-established treatment of PAH. In conclusion, OCA treatment demonstrates cardiopulmonary protective effects, modulating lung vascular remodeling, reducing right ventricular hypertrophy and significantly improving exercise capacity. Thus, OCA can restore the balance between relaxant and contractile pathways in the lung, promoting cardiopulmonary protective actions.

Topics: Animals; Chenodeoxycholic Acid; Exercise Test; Gene Expression Profiling; Gene Expression Regulation; Heart; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Inflammation; Lung; Lung Injury; Male; Monocrotaline; Organ Size; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; RNA, Messenger

Nonalcoholic steatohepatitis (NASH) is the outcome of interactions between overnutrition, energy metabolism, and adipose function. Obeticholic acid (OCA) improves steatosis in patients but for unknown reasons does not resolve NASH pathology. This study therefore investigated OCA effects in Wt mice, which develop obesity with atherogenic dietary feeding, and appetite-dysregulated, Alms1 mutant foz/foz mice fed the same diet, which develop metabolic obesity and diabetes.. OCA (1 mg/kg) was administered orally to female foz/foz mice and Wt littermates from weaning until 28 weeks. Adipose indices, glucose tolerance, and fatty liver pathology were studied. Experiments were repeated with OCA 10 mg/kg.. OCA reduced body weight and hepatic lipids and improved glucose disposal only in Wt mice. OCA limited Wt adipose expansion, altered morphometry in favor of small adipocytes, enhanced expression of genes indicating adipose browning, and reduced crown-like structure number in visceral adipose tissue. foz/foz mice showed more crown-like structures in all compartments; OCA failed to alter adipose morphometry, browning, inflammation, or improve NASH severity, even at 10 mg/kg.. OCA improved adipose indices, glucose tolerance, and steatosis in a milder metabolic phenotype but failed to improve these factors in morbidly obese diabetic mice. These results help explain OCA's limited efficacy to reverse human NASH.

Topics: Adiposity; Animals; Chenodeoxycholic Acid; Diet, Atherogenic; Disease Models, Animal; Fatty Liver; Female; Inflammation; Liver; Mice; Mice, Inbred NOD; Mice, Obese; Obesity; Weight Gain

Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development in liver, kidney and intestine in multiple disease models. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the protective effects of OCA treatment (3 or 10mg/kg/day) on inflammation, tissue remodeling and fibrosis in the bleomycin-induced pulmonary fibrosis rat model. Effects of OCA treatment on morphological and molecular alterations of the lung, as well as remodeling of the alveoli and the right ventricle were also evaluated. Lung function was assessed by measuring airway resistance to inflation. In the acute phase (7days), bleomycin promoted an initial thickening and fibrosis of the lung interstitium, with upregulation of genes related to epithelial proliferation, tissue remodeling and hypoxia. At 28days, an evident increase in the deposition of collagen in the lungs was observed. This excessive deposition was accompanied by an upregulation of transcripts related to the extracellular matrix (TGFβ1, SNAI1 and SNAI2), indicating lung fibrosis. Administration of OCA protected against bleomycin-induced lung damage by suppressing molecular mechanisms related to epithelial-to-mesenchymal transition (EMT), inflammation and collagen deposition, with a dose-dependent reduction of proinflammatory cytokines such as IL-1β and IL-6, as well as TGF-β1 and SNAI1 expression. Pirfenidone, a recently approved treatment for idiopathic pulmonary fibrosis (IPF), significantly counteracted bleomycin-induced pro-fibrotic genes expression, but did not exert significant effects on IL-1β and IL-6. OCA treatment in bleomycin-challenged rats also improved pulmonary function, by effectively normalizing airway resistance to inflation and lung stiffness in vivo. Results with OCA were similar, or even superior, to those obtained with pirfenidone. In conclusion, our results suggest an important protective effect of OCA against bleomycin-induced lung fibrosis by blunting critical mediators in the pathogenesis of IPF.

Topics: Airway Remodeling; Animals; Bleomycin; Chenodeoxycholic Acid; Collagen; Disease Models, Animal; Fibrosis; Gene Expression Profiling; Immunohistochemistry; Inflammation; Lung; Male; Pulmonary Alveoli; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Ventricular Remodeling

In advanced cirrhosis, gut bacterial translocation is the consequence of intestinal barrier disruption and leads to bacterial infection. Bile acid abnormalities in cirrhosis could play a role in the integrity of the intestinal barrier and the control of microbiota, mainly through the farnesoid X receptor. We investigated the long-term effects of the farnesoid X receptor agonist, obeticholic acid, on gut bacterial translocation, intestinal microbiota composition, barrier integrity and inflammation in rats with CCl4-induced cirrhosis with ascites.. Cirrhotic rats received a 2-week course of obeticholic acid or vehicle starting once ascites developed. We then determined: bacterial translocation by mesenteric lymph node culture, ileum expression of antimicrobial peptides and tight junction proteins by qPCR, fecal albumin loss, enteric bacterial load and microbiota composition by qPCR and pyrosequencing of ileum mucosa-attached contents, and intestinal inflammation by cytometry of the inflammatory infiltrate.. Obeticholic acid reduced bacterial translocation from 78.3% to 33.3% (p<0.01) and upregulated the expression of the farnesoid X receptor-associated gene small heterodimer partner. Treatment improved ileum expression of antimicrobial peptides, angiogenin-1 and alpha-5-defensin, tight junction proteins zonulin-1 and occludin, and reduced fecal albumin loss and liver fibrosis. Enteric bacterial load normalized, and the distinctive mucosal microbiota of cirrhosis was reduced. Gut immune cell infiltration was reduced and inflammatory cytokine and Toll-like receptor 4 expression normalized.. In ascitic cirrhotic rats, obeticholic acid reduces gut bacterial translocation via several complementary mechanisms at the intestinal level. This agent could be used as an alternative to antibiotics to prevent bacterial infection in cirrhosis.

Topics: Animals; Chenodeoxycholic Acid; Cytokines; Inflammation; Intestinal Mucosa; Intestines; Liver Cirrhosis, Experimental; Male; Rats; Rats, Sprague-Dawley

Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro, OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis.

Topics: Animals; Apoptosis; Biomarkers; Cell Cycle; Cell Line; Cell Proliferation; Chenodeoxycholic Acid; Cytokines; Disease Models, Animal; Endothelial Cells; Hemodynamics; Hepatic Stellate Cells; Hepatocytes; Humans; Inflammation; Inflammation Mediators; Kupffer Cells; Lipopolysaccharides; Liver; Liver Cirrhosis; Male; Mice; NF-kappa B; NF-KappaB Inhibitor alpha; Portal Pressure; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Thioacetamide; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Resistance

Rabbits with high fat diet (HFD)-induced metabolic syndrome (MetS) developed hypogonadotropic hypogonadism (HH) and showed a reduced gonadotropin-releasing hormone (GnRH) immunopositivity in the hypothalamus. This study investigated the relationship between MetS and hypothalamic alterations in HFD-rabbits. Gonadotropin levels decreased as a function of MetS severity, hypothalamic gene expression of glucose transporter 4 (GLUT4) and interleukin-6 (IL-6). HFD determined a low-grade inflammation in the hypothalamus, significantly inducing microglial activation, expression and immunopositivity of IL-6, as well as GLUT4 and reduced immunopositivity for KISS1 receptor, whose mRNA expression was negatively correlated to glucose intolerance. Correcting glucose metabolism with obetcholic acid improved hypothalamic alterations, reducing GLUT4 and IL-6 immunopositivity and significantly increasing GnRH mRNA, without, however, preventing HFD-related HH. No significant effects at the hypothalamic level were observed after systemic anti-inflammatory treatment (infliximab). Our results suggest that HFD-induced metabolic derangements negatively affect GnRH neuron function through an inflammatory injury at the hypothalamic level.

Topics: Animals; Antibodies, Monoclonal; Biomarkers; Chenodeoxycholic Acid; Diet, High-Fat; Gene Expression Regulation; Glucose Transporter Type 4; Gonadotropin-Releasing Hormone; Immunohistochemistry; Inflammation; Infliximab; Male; Metabolic Syndrome; Neurons; Preoptic Area; Rabbits; Receptors, G-Protein-Coupled; RNA, Messenger

The farnesoid X receptor/bile acid receptor (FXR; NR1H4) is a ligand-activated transcription factor that regulates bile acid and lipid homeostasis, and is highly expressed in enterohepatic tissue. FXR is also expressed in vascular tissue. We have investigated whether FXR regulates inflammation and migration in vascular smooth muscle cells.. The FXR target gene, small heterodimer partner (SHP), was induced in vascular smooth muscle cells after treatment with synthetic FXR ligands, GW4064, or 6alpha-ethyl-chenodeoxycholic acid. FXR ligands induced smooth muscle cell death and downregulated interleukin (IL)-1beta-induced inducible nitric oxide synthase and cyclooxygenase-2 expression. In addition, FXR ligands suppressed smooth muscle cell migration stimulated by platelet-derived growth factor-BB. Reporter gene assays showed that FXR ligands activated an FXR reporter gene and suppressed IL-1beta-induced nuclear factor (NF)-kappaB activation and iNOS in a manner that required functional FXR and SHP.. Our observations suggest that a FXR-SHP pathway may be a novel therapeutic target for vascular inflammation, remodeling, and atherosclerotic plaque stability.

Topics: Animals; Anti-Inflammatory Agents; Becaplermin; Cell Line; Cell Movement; Cell Survival; Cells, Cultured; Chenodeoxycholic Acid; Cyclooxygenase 2; DNA-Binding Proteins; Dose-Response Relationship, Drug; Genes, Reporter; Humans; Inflammation; Interleukin-1beta; Isoxazoles; Ligands; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-kappa B; Nitric Oxide Synthase Type II; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Rats; Receptors, Cytoplasmic and Nuclear; RNA Interference; RNA, Messenger; RNA, Small Interfering; Transcription Factors; Transcription, Genetic; Transfection