Hydroxycarboxylic acid receptor 2 (HCAR2) (HCAR2)

Hydroxycarboxylic acid receptor 2 (HCAR2), commonly known as GPR109A, is a G protein-coupled receptor primarily expressed in adipocytes and immune cells such as macrophages and neutrophils [1, 3]. In adipocytes, GPR109A serves as the high-affinity receptor for niacin (nicotinic acid) and the endogenous ketone body 3-hydroxybutyrate; its activation triggers a Gi-mediated signaling pathway that inhibits adenylate cyclase and reduces cAMP levels [1, 2]. This reduction in cAMP leads to decreased activity of hormone-sensitive lipase, effectively suppressing lipolysis and the release of free fatty acids into the circulation [2, 4]. By lowering the availability of fatty acid substrates for hepatic triglyceride synthesis, GPR109A activation reduces VLDL and LDL levels while significantly increasing HDL cholesterol [1, 9]. Beyond its metabolic role, GPR109A mediates anti-inflammatory effects in the gut and skin, making it a therapeutic target for dyslipidemia, atherosclerosis, and psoriasis [8, 9, 13]. However, its clinical use is often limited by cutaneous flushing, a side effect caused by GPR109A-mediated prostaglandin release in the skin [6, 9].

Other names

GPR109ANiacin receptor 1NIACR1HM74APUMA-GG protein-coupled receptor 109A

Agonism of the Gi/o-coupled receptor leads to the inhibition of adenylate cyclase, which decreases intracellular cAMP levels and subsequently reduces the activity of hormone-sensitive lipase (HSL), thereby inhibiting the hydrolysis of triglycerides into free fatty acids.