obeticholic-acid and Cholestasis--Intrahepatic

Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated maternal circulating bile acid levels and associated dyslipidemia. ICP leads to accumulation of bile acids in the fetal compartment, and the elevated bile acid concentrations are associated with an increased risk of adverse fetal outcomes. The farnesoid X receptor agonist obeticholic acid (OCA) is efficient in the treatment of cholestatic conditions such as primary biliary cholangitis. We hypothesized that OCA administration during hypercholanemic pregnancy will improve maternal and fetal bile acid and lipid profiles. Female C57BL/6J mice were fed either a normal chow diet, a 0.5% cholic acid (CA)-supplemented diet, a 0.03% OCA-supplemented diet, or a 0.5% CA + 0.03% OCA-supplemented diet for 1 wk before mating and throughout pregnancy until euthanization on

Topics: Animals; Bile Acids and Salts; Cecum; Chenodeoxycholic Acid; Cholestasis, Intrahepatic; Cholesterol 7-alpha-Hydroxylase; Dyslipidemias; Female; Gene Expression Regulation; Liver; Mice; Mice, Inbred C57BL; Pregnancy; Pregnancy Complications; RNA-Binding Proteins; RNA, Ribosomal, 16S

Topics: Animals; Chenodeoxycholic Acid; Cholestasis, Intrahepatic; Estrogens; Ethinyl Estradiol; Female; Fetal Growth Retardation; Fetus; Lipid Peroxidation; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Pregnancy; Pregnancy Complications; Signal Transduction

New insights into the molecular mechanisms of bile formation and cholestasis have provided new concepts for pharmacotherapy of cholestatic liver diseases. The major aim in all forms of cholestasis is the reduction of hepatocellular retention of bile acids and other potentially toxic constituents of bile. Reduction of hepatocellular retention may be achieved by drugs that stimulate hepatocellular secretion via the canalicular route into the bile or via the alternative route across the basolateral membrane into the blood, and by drugs that stimulate the hepatocellular metabolism of hydrophobic bile acids to hydrophilic, less toxic metabolites. In cholestatic liver diseases that start with an injury of the biliary epithelium (e.g., primary biliary cirrhosis; PBC), protection of the cholangiocytes against the toxic effects of hydrophobic bile acids is most important. When hepatocellular retention of bile acids has occurred, the inhibition of bile acid-induced apoptosis becomes another target of therapy. Ursodeoxycholic acid protects the biliary epithelium by reducing the toxicity of bile, stimulates hepatobiliary secretion by upregulating transporters and inhibits apoptosis. It is the mainstay of therapy in PBC but of benefit also in a number of other cholestatic liver diseases. New drugs such as 6-ethyl-chenodeoxycholic acid and 24-nor-ursodeoxycholic acid are being evaluated for the treatment of cholestatic liver diseases.

Topics: Bile; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholestasis, Intrahepatic; Chronic Disease; Humans; Liver; Ursodeoxycholic Acid