The receptor TGR5 protects the liver from bile acid... : Hepatology (original) (raw)

Liver Injury/Regeneration

The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice

Péan, Noémie1, 2, 3; Doignon, Isabelle1, 2; Garcin, Isabelle1, 2; Besnard, Aurore1, 2, 4; Julien, Boris1, 2; Liu, Bingkaï1, 2; Branchereau, Sophie5; Spraul, Anne6; Guettier, Catherine7; Humbert, Lydie8; Schoonjans, Kristina9; Rainteau, Dominique8; Tordjmann, Thierry1, 2

1 INSERM U.757, Université Paris Sud, Orsay, France

2 Université Paris Sud, Orsay, France

3 Université Paris Diderot, Sorbonne Paris Cité, Paris, France

4 UPMC Université Paris, Paris, France

5 Service de Chirurgie Pédiatrique, France

6 Service de Biochimie, France

7 Service d'Anatomie Pathologique, Hôpital du Kremlin Bicêtre, Le Kremlin-Bicêtre, France

8 ERL INSERM U.1057,, Faculté de Médecine Pierre et Marie Curie, Paris, France, and UMR 7203, ENS, CNRS, UPMC, Paris, France

9 Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Received 4 February 2013; accepted 8 April 2013

Address reprint requests to: Thierry Tordjmann, M.D., Ph.D., INSERM U.757, Université Paris Sud, Building 443, 91405 Orsay, France. E-mail:[email protected]; fax: +33 1 69 15 58 93.

Potential conflict of interest: Nothing to report.

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.

Additional supporting information may be found in the online version of this article.

View this article online atwileyonlinelibrary.com.

Abstract

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)