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During liver injury and cholestasis, the mechanisms allowing the organ to protect itself with the aim of maintaining biliary homeostasis are not completely understood. Central to their biological roles, bile acids (BAs) and their receptors constitute a signaling network with multiple molecular and cellular impacts on both liver repair and protection from BA overload. BA signal through nuclear [mainly farnesoid X receptor (FXR)] and membrane [mainly G protein-coupled BA receptor 1 (GPBAR-1), aka Takeda G protein-coupled receptor 5 (TGR5)] receptors, in which activation elicits a wide array of biological responses. So far, most of the studies have been focused on FXR signaling as hepato-protective, TGR5 being less explored to this regard. While the liver faces massive and potentially harmful BA overload during cholestasis, it is crucial to understand that BAs induce also protective responses contributing not only to reduce the inflammatory burden, but also to spare liver cells and their repair capacities. Based on the available literature, the TGR5 BA receptor protects the liver in the cholestatic context and counteracts BA overload with the aim of restoring biliary homeostasis mainly through the control of inflammatory processes, biliary epithelial barrier permeability, and BA pool composition. Mouse experimental models of cholestasis reveal that the lack of TGR5 was associated with exacerbated inflammation and necrosis, leaky biliary epithelium, and excessive BA pool hydrophobicity, resulting in biliary cell and parenchymal insult, and compromising optimal restoration of biliary homeostasis and liver repair. There are thus widely opened translational perspectives with the aim of targeting TGR5-related signaling or biological responses to trigger protection of the cholestatic liver.

Liver tissue engineering approaches aim to support drug testing, assistance devices, or transplantation. However, their suitability for clinical application remains unsatisfactory. Herein, we demonstrate the beneficial and biocompatible use of porous pullulan-dextran hydrogel for the self-assembly of hepatocytes and biliary-like cells into functional 3D microtissues. Using HepaRG cells, we obtained 21 days maintenance of engineered liver polarity, functional detoxification and excretion systems, as well as glycogen storage in hydrogel. Implantation on two liver lobes in mice of hydrogels containing 3800 HepaRG 3D structures of 100 ​μm in diameter, indicated successful engraftment and no signs of liver toxicity after one month. Finally, after acetaminophen-induced liver failure, when mice were transplanted with engineered livers on left lobe and peritoneal cavity, the survival rate at 7 days significantly increased by 31.8% compared with mice without cell therapy. These findings support the clinical potential of pullulan-dextran hydrogel for liver failure management.

Background & Aims: As the composition of the bile acid (BA) pool has a major impact on liver pathophysiology, we studied its regulation by the BA receptor Takeda G protein coupled receptor (TGR5), which promotes hepatoprotection against BA overload. Methods: Wild-type, total and hepatocyte-specific TGR5-knockout, and TGR5-overexpressing mice were used in: partial (66%) and 89% extended hepatectomies (EHs) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (CA)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied the impact of TGR5 on: BA composition, liver injury, regeneration and survival. We also performed analyses on the gut microbiota (GM) and gallbladder (GB). Liver BA composition was analysed in patients undergoing major hepatectomy. Results: The TGR5-KO hyperhydrophobic BA composition was not directly related to altered BA synthesis, nor to TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and co-housing experiments, respectively. The TGR5-dependent control of GB dilatation was crucial for BA composition, as determined by experiments including RO treatment and/or cholecystectomy. The poor TGR5-KO post-EH survival rate, related to exacerbated peribiliary necrosis and BA overload, was improved by shifting BAs toward a less toxic composition (CT treatment). After either BDL or a CA-enriched diet with or without cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic liver BA composition was correlated with an unfavourable outcome after hepatectomy. Conclusions: BA composition is crucial for hepatoprotection in mice and humans. We indicate TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions. Lay summary: Through multiple in vivo experimental approaches in mice, together with a patient study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function, and liver protection. We showed that hepatic bile acid composition is crucial for optimal liver repair, not only in mice, but also in human patients undergoing major hepatectomy.

The liver is a highly vascularized organ receiving a dual input of oxygenated blood from the hepatic artery and portal vein. The impact of decreased blood flow on glucose metabolism and how hepatocytes could adapt to this restrictive environment are still unclear. Using the left portal vein ligation (LPVL) rat model, we found that cellular injury was delayed after the onset of liver ischemia. We hypothesized that a metabolic adaptation by hepatocytes to maintain energy homeostasis could account for this lag phase. Liver glucose metabolism was characterized by 13C- and 1H-NMR spectroscopy and analysis of high-energy metabolites. ALT levels and caspase 3 activity in LPVL animals remained normal during the first 12 h following surgery (P

Background & Aims: Bile-acid metabolism and the intestinal microbiota are impaired in alcohol-related liver disease. Activation of the bile-acid receptor TGR5 (or GPBAR1) controls both biliary homeostasis and inflammatory processes. We examined the role of TGR5 in alcohol-induced liver injury in mice. Methods: We used TGR5-deficient (TGR5-KO) and wild-type (WT) female mice, fed alcohol or not, to study the involvement of liver macrophages, the intestinal microbiota (16S sequencing), and bile-acid profiles (high-performance liquid chromatography coupled to tandem mass spectrometry). Hepatic triglyceride accumulation and inflammatory processes were assessed in parallel. Results: TGR5 deficiency worsened liver injury, as shown by greater steatosis and inflammation than in WT mice. Isolation of liver macrophages from WT and TGR5-KO alcohol-fed mice showed that TGR5 deficiency did not increase the pro-inflammatory phenotype of liver macrophages but increased their recruitment to the liver. TGR5 deficiency induced dysbiosis, independently of alcohol intake, and transplantation of the TGR5-KO intestinal microbiota to WT mice was sufficient to worsen alcohol-induced liver inflammation. Secondary bile-acid levels were markedly lower in alcohol-fed TGR5-KO than normally fed WT and TGR5-KO mice. Consistent with these results, predictive analysis showed the abundance of bacterial genes involved in bile-acid transformation to be lower in alcohol-fed TGR5-KO than WT mice. This altered bile-acid profile may explain, in particular, why bile-acid synthesis was not repressed and inflammatory processes were exacerbated. Conclusions: A lack of TGR5 was associated with worsening of alcohol-induced liver injury, a phenotype mainly related to intestinal microbiota dysbiosis and an altered bile-acid profile, following the consumption of alcohol. Lay summary: Excessive chronic alcohol intake can induce liver disease. Bile acids are molecules produced by the liver and can modulate disease severity. We addressed the specific role of TGR5, a bile-acid receptor. We found that TGR5 deficiency worsened alcohol-induced liver injury and induced both intestinal microbiota dysbiosis and bile-acid pool remodelling. Our data suggest that both the intestinal microbiota and TGR5 may be targeted in the context of human alcohol-induced liver injury.