title: Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action.
abstract: Chronic cholestasis and liver inflammation are the two main pathophysiological components of the two major classes of disease - primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) - leading to bile duct destruction and ultimately to cirrhosis and liver failure. Ursodeoxycholic acid (UDCA), initially introduced as a therapeutic approach to counteract the cholestatic components to PBC and PSC, was subsequently shown to exhibit unexpected anti-inflammatory and immunomodulatoty properties. The use of farnesoid X receptor (FXR) and TGR5 agonists in various animal models have confirmed early observations indicating that bile acids are not only toxicants and inflammagens, but also repressors of innate and adaptive immunity. Obeticholic acid is a bile-acid mimetic, with no toxic or inflammagen behavior, that strongly activates FXR to combat the toxic effects of high concentrations of bile acid. Because UDCA is not an FXR agonist, its combination with obeticholic acid could be a promising tool for the treatment of PBC and PSC. In this overview, the biological properties of UDCA, NorUDCA and FXR agonists are highlighted, as well as their overlapping mechanisms of action in inflammatory biliary disorders.
authors.affiliation: Service d'Hépatologie et Centre de Référence des maladies inflammatoires des voies biliaires, Hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg Saint-Antoine, 75571 Paris cedex 12, France. Raoul.poupon@sat.aphp.fr
authors.forename: Raoul
authors.initials: R
authors.lastname: Poupon
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001647:Bile Acids and Salts / Q000819:agonists*; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D015209:Cholangitis, Sclerosing / Q000188:drug therapy* / Q000276:immunology; D019317:Evidence-Based Medicine; D005765:Gastrointestinal Agents / Q000819:agonists*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000893:Anti-Inflammatory Agents; D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D005765:Gastrointestinal Agents; D007155:Immunologic Factors; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D014580:Ursodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated