Potential conflict of interest: Nothing to report.
The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice
Article first published online: 19 AUG 2013
Copyright © 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 4, pages 1451–1460, October 2013
How to Cite
Péan, N., Doignon, I., Garcin, I., Besnard, A., Julien, B., Liu, B., Branchereau, S., Spraul, A., Guettier, C., Humbert, L., Schoonjans, K., Rainteau, D. and Tordjmann, T. (2013), The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. Hepatology, 58: 1451–1460. doi: 10.1002/hep.26463
This study was supported by the Association pour la Recherche contre le Cancer (3435) and by the Agence Nationale de la Recherche (PHYSIO 2007). T.T. is supported by Assistance Publique–Hôpitaux de Paris. The authors thank Galya Vassileva and the Merck Research Laboratories (Kenilworth, NJ) for providing us with the C57Bl/6 Gpbar1−/− mice.
- Issue published online: 1 OCT 2013
- Article first published online: 19 AUG 2013
- Accepted manuscript online: 17 MAY 2013 08:16AM EST
- Manuscript Accepted: 8 APR 2013
- Manuscript Revised: 7 APR 2013
- Manuscript Received: 4 FEB 2013
Many regulatory pathways are involved in liver regeneration after partial hepatectomy (PH) to initiate growth, protect liver cells, and sustain functions of the remnant liver. Bile acids (BAs), whose levels rise in the blood early after PH, stimulate both hepatocyte proliferation and protection, in part through their binding to the nuclear farnesoid X receptor (FXR). However, the effect of the BA receptor, TGR5 (G-protein-coupled BA receptor 1) after PH remains to be studied. Liver histology, hepatocyte proliferation, BA concentrations (plasma, bile, liver, urine, and feces), bile flow and composition, and cytokine production were studied in wild-type (WT) and TGR5 KO (knockout) mice before and after PH. BA composition (plasma, bile, liver, urine, and feces) was more hydrophobic in TGR5 KO than in WT mice. After PH, severe hepatocyte necrosis, prolonged cholestasis, exacerbated inflammatory response, and delayed regeneration were observed in TGR5 KO mice. Although hepatocyte adaptive response to post-PH BA overload was similar in WT and TGR5 KO mice, kidney and biliary adaptive responses were strongly impaired in TGR5 KO mice. Cholestyramine treatment, as well as Kupffer cell depletion, significantly improved the post-PH TGR5 KO mice phenotype. After bile duct ligation or upon a cholic acid–enriched diet, TGR5 KO mice exhibited more severe liver injury than WT as well as impaired BA elimination in urine. Conclusion: TGR5 is crucial for liver protection against BA overload after PH, primarily through the control of bile hydrophobicity and cytokine secretion. In the absence of TGR5, intrahepatic stasis of abnormally hydrophobic bile and excessive inflammation, in association with impaired bile flow adaptation and deficient urinary BA efflux, lead to BA overload-induced liver injury and delayed regeneration. (Hepatology 2013;58:1451–1460)