After PH, the remnant liver adapts to an immediate BA overload[3] by regulating BA synthesis and transport to protect liver cells from BA toxicity.[5, 6] Moreover BA, increasingly viewed as signaling molecules,[9] affect both this adaptive process[5] and liver regeneration

itself, mainly through binding selleckchem to FXR.[4, 6] We investigated the previously unexplored impact of the membrane-bound BA receptor, TGR5, during liver regeneration after PH in mice. Although PH induces a transient BA hepatic overload in WT mice, massive hepatocyte necrosis and cholestasis were observed with delayed liver regeneration only in TGR5 KO mice after PH, suggesting that the ability to challenge BA overload before significant cell damage occurs was, in some way, exceeded in TGR5 KO mice. The lack of TGR5 resulted in more hydrophobic bile and in excessive hepatic inflammation after PH, associated with deficient adaptation of bile composition and flow, as well as insufficient BA efflux in urine, all these factors contributing to excessive BA overload. Cytokine production and release are finely tuned after PH, in a balanced way, to both protect liver cells and promote them for growth-factor–dependent progression into

the cell cycle.[2] The exacerbated post-PH induction of cytokines observed in TGR5 KO mice may thus have contributed to delay regeneration, but also to enhance cholestasis,[6, 26] and to favor hepatocyte necrosis, as see more suggested by KC depletion experiments. However, because early post-PH liver injury was not affected by KC depletion (Fig. 4), inflammation appears more as a worsening, rather than as a triggering, factor in the PH-induced TGR5 KO phenotype. We observed that plasma, liver, bile, and feces from TGR5 KO mice exhibited a more hydrophobic BA

composition, as suggested previously.[17] Interestingly, small heterodimer partner null mice are more susceptible to BDL-induced liver damage than WT mice, because they have a more hydrophobic BA pool.[27] In the same line, mice fed with a lithocholic acid–enriched MCE diet exhibit a hydrophobic bile composition and bile duct obstruction leading to destructive cholangitis with bile infarcts.[28] More recently, FXR-dependent production of fibroblast growth factor 15 has been proposed to protect liver from BA overload by switching BA composition toward a more hydrophilic profile.[29] Thus, too much hydrophobic BA accumulating in the TGR5 KO liver immediately after PH may have led, by itself, to liver injury. This hypothesis is supported by the rescued post-PH phenotype in experiments with BA resin (CT) on the one hand and by the severe phenotypes observed in TGR5 KO mice after BDL or CA-enriched feeding on the other hand.