G‐protein‐coupled bile acid receptor plays a key role in bile acid metabolism and fasting‐induced hepatic steatosis in mice

Abstract

Bile acids are signaling molecules that play a critical role in regulation of hepatic metabolic homeostasis by activating nuclear farnesoid X receptor (Fxr) and membrane G-protein-coupled receptor (Tgr5). The role of FXR in regulation of bile acid synthesis and hepatic metabolism has been studied extensively. However, the role of TGR5 in hepatic metabolism has not been explored. The liver plays a central role in lipid metabolism and impaired response to fasting and feeding contributes to steatosis and non-alcoholic fatty liver and obesity. We have performed a detailed analysis of gallbladder bile acid and lipid metabolism in Tgr5−/− mice in both free-fed and fasted conditions. Lipid profiles of serum, liver and adipose tissues, bile acid composition, energy metabolism, and mRNA and protein expression of the genes involved in lipid metabolism were analyzed. Results showed that deficiency of the Tgr5 gene in mice alleviated fasting-induced hepatic lipid accumulation. Expression of liver oxysterol 7α-hydroxylase (Cyp7b1) in the alternative bile acid synthesis pathway was reduced. Analysis of gallbladder bile acid composition showed marked increase of tauro-cholic acid and decrease of tauro-α and β-muricholic acid in Tgr5−/− mice. Tgr5−/− mice had increased hepatic fatty acid oxidation rate and decreased hepatic fatty acid uptake. Interestingly, fasting induction of fibroblast growth factor 21 (Fgf21) in liver was attenuated. In addition, fasted Tgr5−/− mice had increased activation of hepatic growth hormone-signal transducer and activator of transcription 5 (GH-Stat5) signaling compared to wild type mice. Conclusion This study suggests that TGR5 may play a role in determining bile acid composition and in fasting-induced hepatic steatosis through a novel mechanism involving activation of the GH-Stat5 signaling pathway.

Bile acid receptors link nutrient sensing to metabolic regulation

“…Many of the metabolic improvements, particularly in glucose homeostasis, were attenuated in TGR5 knockout mice after vertical sleeve gastrectomy. Such effects may be partially attributed to altered bile acid composition and action in TGR5 target tissues, which is consistent with altered bile acid metabolism in TGR5 knockout mice (100,111). …”

An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

“…In other tissues, TGR5 has diverse effects that are usually related to metabolism. TGR5 also influences bile acid homeostasis, although the mechanisms are not fully elucidated 67 . While there is no evidence that the gut microbiota or bacterial-derived metabolites alter TGR5 signaling, this possibility has not yet been thoroughly explored.…”

The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

“…Like FXR, TGR5 is involved in BA, glucose, and lipid homeostasis but it also plays a role in increasing energy expenditure via browning of white adipose tissue (WAT) and inducing BAT gene expression in thermogenesis (Scheja and Heeren, 2016). TGR5 KO mice did not significantly change Cyp7a1 gene expression but had altered BA composition (Donepudi et al, 2016). Another study in which vertical sleeve gastrectomy was performed on TGR5 KO mice demonstrates that TGR5 is important in improved glucose control, decreased hepatic steatosis, and increased energy expenditure post-surgery (Ding et al, 2016).…”