title: Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO⁻₃ output.
abstract: Chronic cholangiopathies have limited therapeutic options and represent an important indication for liver transplantation. The nuclear farnesoid X receptor (FXR) and the membrane G protein-coupled receptor, TGR5, regulate bile acid (BA) homeostasis and inflammation. Therefore, we hypothesized that activation of FXR and/or TGR5 could ameliorate liver injury in Mdr2(-/-) (Abcb4(-/-)) mice, a model of chronic cholangiopathy. Hepatic inflammation, fibrosis, as well as bile secretion and key genes of BA homeostasis were addressed in Mdr2(-/-) mice fed either a chow diet or a diet supplemented with the FXR agonist, INT-747, the TGR5 agonist, INT-777, or the dual FXR/TGR5 agonist, INT-767 (0.03% w/w). Only the dual FXR/TGR5 agonist, INT-767, significantly improved serum liver enzymes, hepatic inflammation, and biliary fibrosis in Mdr2(-/-) mice, whereas INT-747 and INT-777 had no hepatoprotective effects. In line with this, INT-767 significantly induced bile flow and biliary HCO 3- output, as well as gene expression of carbonic anhydrase 14, an important enzyme able to enhance HCO 3- transport, in an Fxr-dependent manner. In addition, INT-767 dramatically reduced bile acid synthesis via the induction of ileal Fgf15 and hepatic Shp gene expression, thus resulting in significantly reduced biliary bile acid output in Mdr2(-/-) mice.
  
  
  CONCLUSIONS
  This study shows that FXR activation improves liver injury in a mouse model of chronic cholangiopathy by reduction of biliary BA output and promotion of HCO 3--rich bile secretion.
authors: Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors: Anna
authors: A
authors: Baghdasaryan
authors: Thierry
authors: T
authors: Claudel
authors: Judith
authors: J
authors: Gumhold
authors: Dagmar
authors: D
authors: Silbert
authors: Luciano
authors: L
authors: Adorini
authors: Aldo
authors: A
authors: Roda
authors: Stefania
authors: S
authors: Vecchiotti
authors: Frank J
authors: FJ
authors: Gonzalez
authors: Kristina
authors: K
authors: Schoonjans
authors: Mario
authors: M
authors: Strazzabosco
authors: Peter
authors: P
authors: Fickert
authors: Michael
authors: M
authors: Trauner
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D027321:Anion Transport Proteins / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism; D001660:Biliary Tract Diseases / Q000188:drug therapy* / Q000517:prevention & control; D002793:Cholic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D008107:Liver Diseases / Q000188:drug therapy* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D018709:Statistics, Nonparametric; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000251:Adenosine Triphosphatases; D027321:Anion Transport Proteins; D001647:Bile Acids and Salts; D002793:Cholic Acids; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D000099150:Receptor, Farnesoid X-Activated; C545501:6alpha-ethyl-23(S)-methylcholic acid; C513561:Gpbar1 protein, mouse; C031652:anion-sensitive ATPases