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 a crucial role in bile homeostasis, metabolism, and inflammation, and is involved in various pathways such as regulating liver-gallbladder-gut formation [1].

In primary sclerosing cholangitis (PSC), reduced Tgr5 (Gpbar1) levels in biliary epithelial cells (BECs) of PSC patients and Abcb4-/-mice contribute to a reactive BEC phenotype, aggravating biliary injury and the pathogenesis of sclerosing cholangitis. Restoration of biliary Tgr5-expression levels by norUDCA represents a new mechanism of action [2]. In a mouse model of NAFLD-related cardiovascular disease, activation of Gpbar1 by BAR501 attenuated body weight gain, improved insulin sensitivity, reduced aorta thickness and atherosclerotic lesions, and reshaped the aortic transcriptome [3]. In diabetic cardiomyopathy, cardiomyocyte-specific Tgr5-deleted mice showed increased myocardial lipid accumulation and cardiac dysfunction, indicating the Tgr5-DHHC4 pathway regulates cardiac fatty acid uptake [4].

In conclusion, Gpbar1 is essential for maintaining bile-related physiological functions and metabolism. Gene-knockout mouse models, such as Tgr5-deleted mice, have revealed its role in diseases like sclerosing cholangitis, NAFLD-related cardiovascular disease, and diabetic cardiomyopathy. These findings contribute to understanding the disease mechanisms and may provide new directions for therapeutic strategies.

References:

1. Zhang, Fangling, Xiao, Xiaolin, Li, Yong, Ma, Xiao, Zhao, Yanling. 2022. Therapeutic Opportunities of GPBAR1 in Cholestatic Diseases. In Frontiers in pharmacology, 12, 805269. doi:10.3389/fphar.2021.805269. https://pubmed.ncbi.nlm.nih.gov/35095513/

2. Reich, Maria, Spomer, Lina, Klindt, Caroline, Heikenwalder, Mathias, Keitel, Verena. 2021. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. In Journal of hepatology, 75, 634-646. doi:10.1016/j.jhep.2021.03.029. https://pubmed.ncbi.nlm.nih.gov/33872692/

3. Biagioli, Michele, Marchianò, Silvia, Di Giorgio, Cristina, Cirino, Giuseppe, Fiorucci, Stefano. 2023. Activation of GPBAR1 attenuates vascular inflammation and atherosclerosis in a mouse model of NAFLD-related cardiovascular disease. In Biochemical pharmacology, 218, 115900. doi:10.1016/j.bcp.2023.115900. https://pubmed.ncbi.nlm.nih.gov/37926268/

4. Wang, Hu, Wang, Jiaxing, Cui, Hao, Jiang, Changtao, Xu, Ming. 2024. Inhibition of fatty acid uptake by TGR5 prevents diabetic cardiomyopathy. In Nature metabolism, 6, 1161-1177. doi:10.1038/s42255-024-01036-5. https://pubmed.ncbi.nlm.nih.gov/38698281/