obeticholic-acid and Hypertension--Portal

Farnesoid X nuclear receptor is involved in the regulation of lipid and glucose metabolism, though mainly in the homeostasis of bile acids. Indeed, the agonists of farnesoid X nuclear receptor represent promising drugs. Areas covered: Obeticholic acid, a novel semisynthetic analogue of the naturally occurring bile acid, has led to encouraging preliminary results in both cholestatic and metabolic liver disease. In patients with primary biliary cholangitis, obeticholic acid determines a significant biochemical improvement although the effects on liver fibrosis are lacking. Obeticholic acid has been suggested for the treatment of nonalcoholic liver disease with good laboratory results. In cirrhotic animal models, the drug seems to reduce both portal hypertension and gut bacterial translocation. Expert commentary: The use of obeticholic acid for the treatment of primary biliary cholangitis shows satisfying results. However, some open questions remain unresolved. Herein, we provide an overview of the current knowledge about the use of obeticholic acid in the field of nonviral chronic liver diseases. We tried to give a global point of view using a translational approach.

Topics: Animals; Chenodeoxycholic Acid; Cholangitis, Sclerosing; Disease Models, Animal; Humans; Hypertension, Portal; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Treatment Outcome

Topics: Animals; Azepines; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholestasis; Drug Evaluation, Preclinical; Gastrointestinal Agents; Hepatitis, Autoimmune; Humans; Hypertension, Portal; Indoles; Isoxazoles; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Biliary; Liver Diseases; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid

Portal hypertension (PH) is a common complication of chronic liver disease, and it determines most complications leading to death or liver transplantation in patients with liver cirrhosis. PH results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (a) distortion of the liver vascular architecture and (b) hepatic microvascular dysfunction. Increment in hepatic resistance is latterly accompanied by splanchnic vasodilation, which further aggravates PH. Hepatic microvascular dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSEC). The cross-talk between LSEC and hepatic stellate cells induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis. Therapy for PH aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments, while architectural disruption and fibrosis can be ameliorated by a variety of anti-fibrogenic drugs and anti-angiogenic strategies. Sinusoidal endothelial dysfunction is ameliorated by statins and other drugs increasing NO availability. Splanchnic hyperemia can be counteracted by non-selective beta-blockers (NSBBs), vasopressin analogs and somatostatin analogs. Future treatment of portal hypertension will evolve to use etiological treatments together with anti-fibrotic agents and/or drugs improving microvascular function in initial stages of cirrhosis (pre-primary prophylaxis), while NSBBs will be added in advanced stages of the disease.

Topics: Acetates; Antioxidants; Biopterins; Chenodeoxycholic Acid; Cyclopropanes; Endothelial Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Portal; Leukotriene Antagonists; Liver Circulation; Liver Cirrhosis; Microvessels; Molecular Targeted Therapy; Naphthalenes; Neovascularization, Pathologic; Propionates; Quinolines; Sulfides; Vascular Resistance

Portal hypertension is a frequent pathological symptom occurring especially in hepatic fibrosis and cirrhosis. Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous in vitro study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis-related portal hypertension still requires clarification. In this study, gain- and loss-of-function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl

Topics: Animals; Artemisinins; Carbon Tetrachloride; Cell Death; Chenodeoxycholic Acid; Gene Expression; Hepatic Stellate Cells; Hepatocytes; Humans; Hypertension, Portal; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Portal Vein; Pregnenediones; Protective Agents; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear

The farnesoid X receptor (FXR) is a nuclear bile acid receptor involved in bile acid homeostasis, hepatic and intestinal inflammation, liver fibrosis, and cardiovascular disease. We studied the effect of short-term treatment with obeticholic acid (INT-747), a potent selective FXR agonist, on intrahepatic hemodynamic dysfunction and signaling pathways in different rat models of cirrhotic portal hypertension (PHT). For this, thioacetamide (TAA)-intoxicated and bile-duct-ligated (BDL) rats were used as models. After gavage of two doses of 30 mg/kg of INT-747 or vehicle within 24 hours, in vivo hemodynamics were assessed. Additionally, we evaluated the direct effect of INT-747 on total intrahepatic vascular resistance (IHVR) and intrahepatic vascular tone (endothelial dysfunction and hyperresponsiveness to methoxamine) by means of an in situ liver perfusion system and on hepatic stellate cell contraction in vitro. FXR expression and involved intrahepatic vasoactive pathways (e.g., endothelial nitric oxide synthase [eNOS], Rho-kinase, and dimethylarginine dimethylaminohydrolase [DDAH]) were analyzed by immunohistochemistry, reverse-transcriptase polymerase chain reaction, or western blotting. In both cirrhotic models, FXR expression was decreased. Treatment with INT-747 in TAA and BDL reactivated the FXR downstream signaling pathway and decreased portal pressure by lowering total IHVR without deleterious systemic hypotension. In the perfused TAA and BDL cirrhotic liver, INT-747 improved endothelial vasorelaxation capacity, but not hyperresponsiveness. In both groups, this was associated with an increased eNOS activity, which, in TAA, related to down-regulation of Rho-kinase and in BDL to up-regulation of DDAH-2.. FXR agonist INT-747 improves PHT in two different rat models of cirrhosis by decreasing IHVR. This hemodynamic effect relates to increased intrahepatic eNOS activity by pathways that differ depending on the etiology of cirrhosis.

Topics: Animals; Chenodeoxycholic Acid; Disease Models, Animal; Down-Regulation; Drug Evaluation, Preclinical; Hypertension, Portal; Liver Cirrhosis; Male; Nitric Oxide Synthase Type III; Random Allocation; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Signal Transduction

Topics: Animals; Chenodeoxycholic Acid; Hypertension, Portal; Male; Signal Transduction