Baghdasaryan, AnnaClaudel, ThierryGumhold, JudithSilbert, DagmarAdorini, LucianoRoda, AldoVecchiotti, StefaniaGonzalez, Frank J.Schoonjans, KristinaStrazzabosco, MarioFickert, PeterTrauner, Michael2011-11-152011-11-152011-11-15201110.1002/hep.24537https://infoscience.epfl.ch/handle/20.500.14299/72618WOS:000295577200022Chronic 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. CONCLUSION: 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.Transmembrane Carbonic-AnhydraseHuman Gallbladder EpitheliumBile-Acid-HomeostasisNuclear ReceptorSclerosing CholangitisCl-/Hco3-ExchangerUrsodeoxycholic AcidTransport MetabolonRat HepatocytesKnockout MiceDual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO⁻₃ outputtext::journal::journal article::research article