GPR109A (PUMA-G/HM74A) mediates nicotinic acid–induced flushing

Abstract

Nicotinic acid (niacin) has long been used as an antidyslipidemic drug.Its special profile of actions, especially the rise in HDL-cholesterol levels induced by nicotinic acid, is unique among the currently available pharmacological tools to treat lipid disorders.Recently, a G-protein-coupled receptor, termed GPR109A (HM74A in humans, PUMA-G in mice), was described and shown to mediate the nicotinic acid-induced antilipolytic effects in adipocytes.One of the major problems of the pharmacotherapeutical use of nicotinic acid is a strong flushing response.This side effect, although harmless, strongly affects patient compliance.In the present study, we show that mice lacking PUMA-G did not show nicotinic acid-induced flushing.In addition, flushing in response to nicotinic acid was also abrogated in the absence of cyclooxygenase type 1, and mice lacking prostaglandin D 2 (PGD 2 ) and prostaglandin E 2 (PGE 2 ) receptors had reduced flushing responses.The mouse orthologue of GPR109A, PUMA-G, is highly expressed in macrophages and other immune cells, and transplantation of wild-type bone marrow into irradiated PUMA-G-deficient mice restored the nicotinic acid-induced flushing response.Our data clearly indicate that GPR109A mediates nicotinic acid-induced flushing and that this effect involves release of PGE 2 and PGD 2 , most likely from immune cells of the skin. ResultsTo study the mechanism of nicotinic acid-induced flushing in genetic mouse models, we established a procedure to determine Nonstandard abbreviations used: [Ca 2+ ]i, intracellular [Ca 2+ ]; DP, PGD2 receptor; EP2, type 2 PGE2 receptor; IP, PGI2 receptor; LD, laser Doppler; LDF, LD flux; PLA2, phospholipase A2; PGD2, prostaglandin D2; PGE2, prostaglandin E2; PGI2, prostaglandin I2; PUMA-G, protein upregulated in macrophages by interferon-g.