obeticholic-acid and Metabolic-Diseases

Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global Fxr-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in Apc

Topics: Animals; Antineoplastic Agents; Bile Acids and Salts; Biomarkers; Chenodeoxycholic Acid; Gastrointestinal Agents; Gastrointestinal Microbiome; Gastrointestinal Neoplasms; Humans; Liver Neoplasms; Metabolic Diseases; Mice; Receptors, Cytoplasmic and Nuclear; Signal Transduction

Farnesoid X receptor (FXR), a nuclear receptor mainly expressed in enterohepatic tissues, is a master for bile acid, lipid and glucose homeostasis. Additionally, it acts as a cell protector with unclear mechanism but may be implicated in combating against inflammation, fibrosis and cancers. FXR is thus accepted as a promising target particularly for the enterohepatic diseases, and numerous FXR modulators have been patented and developed.. This review provides an update on the development of FXR modulators for enterohepatic diseases and offers an in-depth perspective on new strategies for the development of novel FXR modulators.. Despite the development of numerous FXR modulators, which culminated in the successful launch of obeticholic acid (OCA), it remains a matter of debate on how the function of FXR should be exploited for therapeutic purposes. The improvement for obesity achieved by either FXR agonists or antagonists is still in confusion. Whether the side effect of pruritus induced by OCA could be exempted for non-steroidal FXR agonists needs further validation. Apart from the development of conventional FXR ligands, emerging evidence support that restoration of FXR protein level may represent a new strategy in targeting FXR for enterohepatic and metabolic diseases.

Topics: Animals; Chenodeoxycholic Acid; Drug Design; Humans; Ligands; Liver Diseases; Metabolic Diseases; Patents as Topic; Receptors, Cytoplasmic and Nuclear

6-ethyl-chedeoxycholic acid (6E-CDCA) is a farnesoid X receptor (FXR) ligand endowed with agonistic activity under development for treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) and liver-related metabolic disorders including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). FXR is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps of bile acid uptake, metabolism and excretion. 6E-CDCA has been investigated in preclinical models of cholestasis, liver fibrosis and diet-induced atherosclerosis. In a phase II clinical trial in patients with PBC, 6E-CDCA met the primary endpoint of a reduction in alkaline phosphatase levels but safety data indicated that the drug exacerbated pruritus, one of the main symptoms of PBC, suggesting that 6E-CDCA or FXR are mediators of pruritus in humans. Treatment of patients with diabetes and liver steatosis resulted in amelioration of insulin sensitivity despite a reduction a slight reduction in HDL and increased levels of LDL were observed. These side effects on bile acids and lipid metabolism were all predicted by pre-clinical studies, suggesting that potent FXR ligands hold promise but potential side effects might limit their development.

Topics: Animals; Chenodeoxycholic Acid; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Hypoglycemic Agents; Liver Diseases; Metabolic Diseases; Receptors, Cytoplasmic and Nuclear