Free fatty acid receptor 3, Free fatty acid receptor 2, and Hydroxycarboxylic acid receptor 2 (GPR41, GPR43, and GPR109A)

GPR41 (Free fatty acid receptor 3), GPR43 (Free fatty acid receptor 2), and GPR109A (Hydroxycarboxylic acid receptor 2) are a group of G protein-coupled receptors that serve as primary sensors for microbial metabolites, specifically short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate [Nature Reviews Drug Discovery, 2011]. These receptors are predominantly expressed on intestinal epithelial cells and various immune cells, including neutrophils, macrophages, and regulatory T cells, where they facilitate the communication between the gut microbiota and the host immune system [Science, 2013]. GPR41 and GPR43 are involved in regulating energy expenditure and the secretion of metabolic hormones such as glucagon-like peptide-1 (GLP-1), while GPR109A acts as a high-affinity receptor for niacin and a low-affinity receptor for butyrate to exert potent anti-inflammatory and tumor-suppressive effects in the colon [Immunity, 2014]. Dysregulation of these signaling pathways is strongly linked to the pathogenesis of inflammatory bowel diseases, metabolic syndrome, and colorectal cancer [Frontiers in Endocrinology, 2020]. Consequently, they are viewed as promising therapeutic targets for treating chronic inflammatory and metabolic disorders, although drug development is complicated by the need for tissue specificity and the management of side effects like niacin-induced flushing [Pharmacological Reviews, 2018].

Other names

FFAR3FFAR2HCAR2NIACR1HM74AGPR41GPR43GPR109AFree fatty acid receptor 3Free fatty acid receptor 2Hydroxycarboxylic acid receptor 2

Activation of GPR41, GPR43, and GPR109A triggers intracellular signaling through Gi/o and Gq proteins, leading to decreased cAMP levels and increased calcium mobilization, which modulates immune cell function and metabolic hormone release [Le Poul et al., 2003; Thangaraju et al., 2009].