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

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 overloadinduced liver injury and delayed regeneration.

Les lésions hépatiques induites par la cholestase : le rôle de S1PR2

“…À l'inverse, l'activation du récepteur TGR5 par les acides biliaires secondaires est connue pour ses propriétés protectrices et favorisant la régénération en condition de surcharge en acides biliaires. Elle pourrait ainsi s'opposer à l'évolution vers la fibrose [4,6] (Figure 2 …”

“…L'activation de TGR5 par les acides biliaires secondaires stimule la prolifération et inhibe l'apoptose des cholangiocytes [5]. Au niveau des macrophages, TGR5 limite la production de cytokines pro-inflammatoires [6]. Ainsi, les récepteurs FXR et TGR5 sont aujourd'hui associés à la régénéra-tion et la protection hépatiques en cas de surcharge en acides biliaires [3,4,6], et pourraient représenter des cibles théra-peutiques intéressantes lors de certaines pathologies biliaires.…”

“…Au niveau des macrophages, TGR5 limite la production de cytokines pro-inflammatoires [6]. Ainsi, les récepteurs FXR et TGR5 sont aujourd'hui associés à la régénéra-tion et la protection hépatiques en cas de surcharge en acides biliaires [3,4,6], et pourraient représenter des cibles théra-peutiques intéressantes lors de certaines pathologies biliaires. Le récepteur S1PR2, fortement exprimé dans le foie, est l'un des cinq récepteurs membranaires de la S1P (sphingosine-1-phosphate).…”

The role of bile salts in liver regeneration

“…PHx in Tgr5 -/-mice resulted in prolonged elevations of circulating and hepatic bile salts, severe necrosis, an aggravated inflammatory response, and delayed liver regeneration [54]. The liver injury observed in hepatectomized Tgr5 -/-mice is likely caused by bile salt-induced toxicity [55]. Thus, although the mechanisms are incompletely understood, Tgr5 appears to be important for protecting the remnant liver against the hepatotoxicity related to the transient bile salt overload after PHx.…”

“…Cholestasis is an established risk factor for PLF [59], and patients with jaundice due to bile duct obstruction or parenchymal liver disease have increased morbidity rates following PHx [59,60]. This implicates dysregulated bile salt homeostasis and bile salt toxicity in the defective regenerative response observed in patients with PLF, as mirrored in impaired liver regeneration in Fxr and Tgr5 knockout models [26,47,48,54,55]. Enhanced Kupffer cell activation is thought to occur in PLF, resulting in an excessive inflammatory response and hepatocyte death through pro-inflammatory cytokine triggered pathways [60].…”