GPR109A (PUMA-G/HM74A) mediates nicotinic acid–induced flushing
Zoltán Benyó, … , Klaus Pfeffer, Stefan Offermanns
Zoltán Benyó, … , Klaus Pfeffer, Stefan Offermanns
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3634-3640. https://doi.org/10.1172/JCI23626.
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Research Article Dermatology

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 D2 (PGD2) and prostaglandin E2 (PGE2) 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 PGE2 and PGD2, most likely from immune cells of the skin.

Authors

Zoltán Benyó, Andreas Gille, Jukka Kero, Marion Csiky, Marie Catherine Suchánková, Rolf M. Nüsing, Alexandra Moers, Klaus Pfeffer, Stefan Offermanns

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PUMA-G is expressed in the skin and in various immune cells. (A) Norther...
PUMA-G is expressed in the skin and in various immune cells. (A) Northern blot analysis of PUMA-G mRNA in the ear and brown adipose tissue (BAT) of PUMA-G+/+ (WT) and PUMA-G–/– (KO) animals. 18s, ribosomal RNA used as control. (B) RT-PCR of cDNAs from different tissues prepared from PUMA-G+/+ (WT) and PUMA-G–/– (KO) mice using PUMA-G– or GAPDH-specific primers. (C) Expression of PUMA-G in dermal MHC class II–positive cells, dendritic cells, and peritoneal macrophages. (D) Effect of NA (100 μM) and ATP (10 μM) on the [Ca2+]i in macrophages prepared from wild-type or PUMA-G–deficient mice. Values on the y axis indicate the measured 340/380-nm fluorescence ratio as an indicator of the intracellular-free [Ca2+].