Tgr5-/- mice are protected from ethanol-induced metabolic alterations through enhanced leptin and Fgf21 signaling.

BACKGROUND

Alcohol-associated liver disease (ALD) is caused by chronic use of alcohol and ranges from hepatic steatosis to fibrosis and cirrhosis. Bile acids are physiological detergents that also regulate hepatic glucose and lipid homeostasis by binding to several receptors. One such receptor, Takeda G protein-coupled receptor 5 (TGR5), may represent a therapeutic target for ALD. Here, we used a chronic 10-day + binge ethanol-feeding model in mice to study the role of TGR5 in alcohol-induced liver injury.

METHODS

Female C57BL/6J wild-type mice and Tgr5-/- mice were pair-fed Lieber-DeCarli liquid diet with ethanol (5% v/v) or isocaloric control diet for 10 days followed by a gavage of 5% ethanol or isocaloric maltose control, respectively, to represent a binge-drinking episode. Tissues were harvested 9 hours following the binge, and metabolic phenotypes were characterized through examination of liver, adipose, and brain mechanistic pathways.

RESULTS

Tgr5-/- mice were protected from alcohol-induced accumulation of hepatic triglycerides. Interestingly, liver and serum levels of Fgf21 were significantly increased during ethanol feeding in Tgr5-/- mice, as was phosphorylation of Stat3. Parallel to Fgf21 levels, increased leptin gene expression in white adipose tissue and increased leptin receptor in liver were detected in Tgr5-/- mice fed ethanol diet. Adipocyte lipase gene expression was significantly increased in Tgr5-/- mice regardless of diet, whereas adipose browning markers were also increased in ethanol-fed Tgr5-/- mice, indicating potential for enhanced white adipose metabolism. Lastly, hypothalamic mRNA targets of leptin, involved in the regulation of food intake, were significantly increased in Tgr5-/- mice fed ethanol diet.

CONCLUSIONS

Tgr5-/- mice are protected from ethanol-induced liver damage and lipid accumulation. Alterations in lipid uptake and Fgf21 signaling, and enhanced metabolic activity of white adipose tissue, may mediate these effects.