Hydroxycarboxylic acid receptor 2

Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and formerly as HM74A, is a G protein-coupled receptor that in humans is encoded by the HCA2 gene. HCA2 is a member of the hydroxycarboxylic acid family of receptors and is involved in the regulation of lipid metabolism and immune responses. It is activated by certain types of hydroxy carboxylic acids, the most notable of which is nicotinic acid (niacin), a well-known lipid-lowering agent used to manage dyslipidemia and decrease cardiovascular risk.

Function

HCA2 is primarily expressed in adipose tissue, the spleen, the immune system, and the skin. Upon activation by its ligands, such as nicotinic acid, HCA2 inhibits adenylate cyclase activity, leading to a decrease in intracellular cyclic AMP levels. This signaling pathway is involved in the anti-lipolytic effect of nicotinic acid, which results in decreased free fatty acid (FFA) levels in plasma and, consequently, reduced synthesis of triglycerides in the liver. The activation of HCA2 also induces the release of prostaglandin D2 in the skin, which is responsible for the vasodilation and flushing commonly associated with high doses of nicotinic acid.

In addition to its metabolic effects, HCA2 plays a role in the immune system. It has been shown to modulate the inflammatory response and has potential therapeutic implications in inflammatory and autoimmune diseases.

Clinical Significance

The role of HCA2 in lipid metabolism makes it a target for the treatment of dyslipidemia. Niacin, through its activation of HCA2, can significantly reduce levels of LDL cholesterol and triglycerides while increasing HDL cholesterol levels. However, the use of niacin is limited by its side effects, particularly the flushing caused by prostaglandin D2 release, which is mediated through HCA2 activation.

Recent research has also focused on the potential anti-inflammatory and neuroprotective roles of HCA2. Activation of HCA2 has been shown to have protective effects in models of neurodegenerative diseases and is being explored as a therapeutic target for conditions such as multiple sclerosis and Alzheimer's disease.

Ligands

Several endogenous and synthetic ligands for HCA2 have been identified. Endogenous ligands include nicotinic acid and certain beta-hydroxybutyric acids. Synthetic agonists are being developed to exploit the therapeutic potential of HCA2 activation with fewer side effects than niacin.

See Also

• G protein-coupled receptor
• Lipid metabolism
• Inflammatory response
• Nicotinic acid
• Dyslipidemia