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Autoimmune, Cholestatic and Biliary Disease
Article first published online: 27 SEP 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 4, pages 1303–1312, October 2011
How to Cite
Baghdasaryan, A., Claudel, T., Gumhold, J., Silbert, D., Adorini, L., Roda, A., Vecchiotti, S., Gonzalez, F. J., Schoonjans, K., Strazzabosco, M., Fickert, P. and Trauner, M. (2011), Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2−/− (Abcb4−/−) mouse cholangiopathy model by promoting biliary HCO output. Hepatology, 54: 1303–1312. doi: 10.1002/hep.24537
Potential conflict of interest: Dr. Adornini owns stock in Intercept. Dr. Trauner is a consultant for Phenex. He is on the speakers' bureau of Falk and received grants from Intercept.
This work was supported by the Austrian Science Foundation (grant nos. P18613-B05, P19118, and SFB 3008; to M.T.), the Swiss National Science Foundation (grant no. SNF 31003A-125487/1; to K.S.), and by the PhD Program of the Medical University of Graz (to A.B.).
- Issue published online: 27 SEP 2011
- Article first published online: 27 SEP 2011
- Accepted manuscript online: 11 JUL 2011 12:29PM EST
- Manuscript Accepted: 23 JUN 2011
- Manuscript Received: 12 MAY 2011
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 output, as well as gene expression of carbonic anhydrase 14, an important enzyme able to enhance HCO 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-rich bile secretion. (HEPATOLOGY 2011;54:1303–1312)