Hydroxycarboxylic acid receptor 2 (HCA2) (HCA2)

Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A or the niacin receptor, is a G protein-coupled receptor (GPCR) primarily expressed in adipocytes and various immune cells, including macrophages and neutrophils [1, 7]. It serves as a metabolic sensor, activated endogenously by the ketone body beta-hydroxybutyrate and the short-chain fatty acid butyrate [4, 8]. Upon activation, HCA2 couples to Gi proteins to inhibit adenylyl cyclase, leading to a decrease in intracellular cAMP levels and a subsequent reduction in lipolysis in adipose tissue [2, 15]. This mechanism is the basis for the clinical use of niacin (nicotinic acid) in treating dyslipidemia, as it lowers circulating free fatty acids and improves lipid profiles [1, 12]. Beyond metabolism, HCA2 plays a significant role in mediating anti-inflammatory effects; for instance, its activation by monomethyl fumarate is linked to the therapeutic benefits seen in multiple sclerosis [12, 17]. However, pharmacological activation of HCA2 is frequently associated with cutaneous flushing, a side effect mediated by prostaglandin D2 release from skin cells [4, 15]. Despite this challenge, HCA2 remains a target of interest for cardiovascular, neurodegenerative, and inflammatory diseases due to its dual role in metabolic regulation and immune modulation [15, 16].

Other names

GPR109AHM74ANIACR1Niacin receptor 1PUMA-GHCAR2Nicotinic acid receptor

Agonist-mediated activation of Gi-protein signaling, leading to inhibition of adenylyl cyclase and reduction of intracellular cAMP levels.