We thank our colleagues Holly L. Hanson and Huiming Hon
for critical discussions. Additional supporting information may be found in the online version of this article. ”
“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, PF-01367338 and cytokine production were studied in wild-type (WT) and TGR5 KO (knockout) mice before and after PH. BA composition learn more (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 PD184352 (CI-1040) regeneration. (Hepatology 2013;58:1451–1460) After a two-thirds partial hepatectomy (PH), the rodent liver is restored to its initial mass within a few days, during which time a complex array of proliferative and hepatoprotective signaling cascades operates, involving cytokines, growth factors, and other paracrine and endocrine agonists.[1, 2] One of the first physiological consequences of PH is an immediate increase in blood bile acid (BA) concentration, reported to signal, by farnesoid X receptor (FXR) stimulation, for the need of hepatocyte division and protection. After PH, the remnant liver adapts to this immediate BA overload by down-regulating BA synthesis and uptake through FXR-dependent pathways.