Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO⁻₃ output

Hepatology. 2011 Oct;54(4):1303-12. doi: 10.1002/hep.24537.


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.

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.

Publication types

  • Comparative Study

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Adenosine Triphosphatases / metabolism*
  • Analysis of Variance
  • Animals
  • Anion Transport Proteins / metabolism*
  • Bile Acids and Salts / metabolism
  • Biliary Tract Diseases / drug therapy*
  • Biliary Tract Diseases / prevention & control
  • Cholic Acids / pharmacology*
  • Disease Models, Animal
  • Liver Diseases / drug therapy*
  • Liver Diseases / prevention & control
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Random Allocation
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Statistics, Nonparametric


  • 6alpha-ethyl-23(S)-methylcholic acid
  • ATP Binding Cassette Transporter, Subfamily B
  • Anion Transport Proteins
  • Bile Acids and Salts
  • Cholic Acids
  • Gpbar1 protein, mouse
  • P-glycoprotein 2
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, G-Protein-Coupled
  • farnesoid X-activated receptor
  • Adenosine Triphosphatases
  • anion-sensitive ATPases