Hepatobiliary and Cardiovascular Effects Limit

TGR5 is a Gs-coupled GPCR activated by both primary and secondary bile acids (i.e. taurolithocholic acid) encoded by the G protein-coupled bile acid receptor 1 (GPBAR1) gene. The biological role of TGR5 is a function of both its pattern of expression and its ability to increase cellular cAMP [1-3]. Activation of TGR5 in intestinal enteroendocrine cells leads to secretion of GLP-1 and other related incretins, through a mechanism similar to GPR119 [4]. In monocytes/macrophages and dendritic cells (Mo/M /DC), TGR5 activation leads to decreases in LPS-induced Th1 cytokines like TNF-α and IL12 [5]. Together, these functions make TGR5 an attractive target in the treatment of type 2 diabetes, where strategies to enhance GLP-1 [6] and mitigate chronic inflammation [7-9] are already demonstrating benefit in the clinic. While several pharmaceutical organizations have pursued TGR5 agonists, no TGR5 drug has been approved for diabetes or metabolic diseases indication.