The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice.
Résumé
Background and aims. 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 (BA), 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 impact of the BA receptor TGR5 (G Protein-Coupled BA Receptor 1, GPBAR1) after PH remains to be studied. Methods. Liver histology, hepatocyte proliferation, BA concentrations (plasma, bile, liver, urine, feces), bile flow and composition, and cytokine production were studied in wild type (WT) and TGR5-KO mice, before and after PH. Results. BA composition (plasma, bile, liver, urine, 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. While 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 cholic acid-enriched diet, TGR5-KO mice exhibited more severe liver injury than WT, and impaired BA elimination in urines. 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.).