Deficiency of both farnesoid X receptor and Takeda G protein‐coupled receptor 5 exacerbated liver fibrosis in mice

Abstract

Activation of the nuclear bile acid receptor farnesoid X receptor (FXR) protects against hepatic inflammation and injury, while Takeda G protein‐coupled receptor 5 (TGR5) promotes adipose tissue browning and energy metabolism. Here, we examined the physiological and metabolic effects of the deficiency of these two bile acid receptors on hepatic metabolism and injury in mice. Fxr/Tgr5 double knockout mice (DKO) were generated for metabolic phenotyping. Male DKO mice fed chow diet had reduced liver lipid levels but increased serum cholesterol levels. Liver Cyp7a1 activity and Cyp8b1 mRNA levels were induced, while ileum FXR target genes were suppressed in DKO mice compared to WT mice. Bile acid pool size was increased in DKO mice, with increased tauro‐cholic acid and decreased tauro‐muricholic acids. RNA sequencing analysis of the liver transcriptome revealed that bile acid synthesis and fibrosis gene expression levels are increased in chow‐fed DKO mice compared to WT mice and the top regulated pathways are involved in steroid/cholesterol biosynthesis, liver cirrhosis and connective tissue disease. Cholestyramine treatment further induced Cyp7a1 mRNA and protein in DKO mice, and increased bile acid pool size, while cholic acid also induced Cyp7a1 in DKO mice, suggesting impaired bile acid feedback regulation. Western diet containing 0.2% cholesterol increased oxidative stress and markers of liver fibrosis, but not hepatic steatosis in DKO mice. In conclusion, FXR and TGR5 play critical roles in protecting the liver from inflammation and fibrosis. Deficiency of both of these bile acid receptors in mice increased cholic acid synthesis and bile acid pool, liver fibrosis and inflammation. FXR and TGR5 double knockout mice may be a novel mouse model for liver fibrosis.

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