Gpbar1, also known as TGR5, is a transmembrane G protein-coupled receptor for bile acids. It is widely expressed in multiple tissues in humans and rodents. Gpbar1 plays important roles in bile homeostasis, metabolism, and inflammation, and is involved in various pathways related to liver-gallbladder-gut formation [1,4].

In a genetic mouse model of primary sclerosing cholangitis (PSC), reduced TGR5 (Gpbar1) levels in biliary epithelial cells (BECs) promoted a reactive BEC phenotype and aggravated biliary injury, contributing to PSC pathogenesis. Restoration of biliary TGR5-expression levels by norUDCA represents a new mechanism of action for this drug [2]. In Apolipoprotein E deficient (ApoE-/ -) mice fed a high-fat diet and fructose, activation of Gpbar1 by BAR501 attenuated body weight gain, ameliorated insulin sensitivity, reduced aorta thickness and atherosclerotic lesions, and reshaped the aortic transcriptome [3].

In conclusion, Gpbar1 is crucial for maintaining bile-related physiological functions and metabolic balance. Mouse models, especially gene-knockout models like those in PSC and ApoE-/-mice, have revealed its significant roles in cholestatic diseases and NAFLD-related cardiovascular diseases, providing insights into potential therapeutic strategies for these diseases.