Farnesoid X receptor and G protein-coupled bile acid receptor 1 (FXR and TGR5)

The bile acid receptors FXR (Farnesoid X Receptor) and TGR5 (G protein-coupled bile acid receptor 1) are critical sensors that coordinate metabolic responses to bile acid fluctuations. FXR is a nuclear receptor that functions as a ligand-activated transcription factor, primarily regulating the expression of genes involved in bile acid synthesis, such as CYP7A1, and transport in the liver and ileum [1, 4]. In contrast, TGR5 is a plasma membrane-bound G protein-coupled receptor that mediates rapid signaling effects, including the release of glucagon-like peptide-1 (GLP-1) from enteroendocrine cells and the stimulation of energy expenditure in brown adipose tissue [2, 5]. Together, these receptors form a dual-layered sensing system that maintains systemic lipid, glucose, and energy homeostasis [3]. Dysregulation of this system is implicated in the development of metabolic dysfunction-associated steatohepatitis (MASH), primary biliary cholangitis (PBC), and type 2 diabetes [3, 6]. Pharmacological strategies often employ dual agonists, such as INT-767, to leverage the complementary effects of both receptors in reducing hepatic steatosis, inflammation, and fibrosis [6]. However, therapeutic development faces challenges such as drug-induced pruritus and adverse changes in cholesterol profiles [6].

Other names

NR1H4GPBAR1G-protein coupled bile acid receptor 1Nuclear receptor subfamily 1 group H member 4M-BARBG37GPCR19Bile acid receptor

Dual agonism of the nuclear receptor FXR and the membrane receptor TGR5 to suppress bile acid synthesis, promote GLP-1 secretion, and reduce hepatic inflammation and fibrosis.