Niacin receptor 1

Niacin receptor 1 (NIACR1), also known as GPR109A and HCA2, is a protein which in humans is encoded by the NIACR1 gene.

Function

NIACR1 is a high-affinity G_i/G_o-coupled G protein-coupled receptor (GPCR) for nicotinic acid (niacin), and is a member of the nicotinic acid receptor family of GPCRs. NIACR1 activation inhibits lipolytic and atherogenic activity (i.e., it inhibits the breakdown of fats and the development of atherosclerosis), induces vasodilation (i.e., the dilation of blood vessels), and is responsible for niacin-induced flushing.

5-oxo-ETE

The mouse ortholog of NIACR1, Niacr1, has recently been proposed to mediate the ability of 5-oxo-ETE, a member of the 5-HETE family of eicosanoids, to stimulate the production of steroidogenic acute regulatory protein mRNA, Steroidogenic acute regulatory protein, and thereby progesterone in mouse cultured MA-10 Leydig cells. Human tissues respond to 5-oxo-ETE and other 5-HETE family members though the OXER1 G protein-coupled receptor. The roles, if any, of Niacr1 in the response of leydig cells to other 5-HETE family members, of Niacr1 in the response of other mouse cells to 5-HETE family members, and the role of NIACR1 in the response of human tissues to 5-HETE family members has not been determined.

Clinical significance

NIACR1 is an important biomolecular target of niacin which is a widely prescribed drug for the treatment of dyslipidemia and to increase HDL cholesterol but whose therapeutic use is limited by flushing. In NIACR1 knockout mice, the effects of niacin on both lipids and flushing is eliminated. Furthermore, in arrestin beta 1 knockout mice, niacin's effect on flushing is greatly reduced while the lipid modifying effects are maintained. At high doses, niacin produces marked anti-inflammatory effects in a variety of tissues – including the brain, gastrointestinal tract, skin, and vascular tissue – through activation of NIACR1. Niacin has also been shown to attenuate neuroinflammation in part through NIACR1 binding; consequently, NIACR1 has been identified as a potential therapeutic target for treating neuroimmune disorders such as multiple sclerosis and Parkinson's disease.

The precise mechanism of action of niacin therapeutic effects has not been fully elucidated, but appears to work in part through activation of NIACR1 which reduces the levels of intracellular cAMP thereby inhibiting lipolysis in adipocytes. In contrast, the flushing effect is due to NIACR1 activation of ERK 1/2 MAP kinase mediated by arrestin beta 1. Activation of MAP kinase in turn causes release of prostaglandin D2 from Langerhans cells in the skin.

Ligands

Full agonists of NIACR1 include:

• Niacin (also known as vitamin B3 and nicotinic acid)
• Butyric acid and butyrate