GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing
GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing
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DOI：
10.1172/jci23626
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发表时间：
2005-12-01
影响因子：
15.9
通讯作者：
Offermanns, S
中科院分区：
文献类型：
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作者：
Benyó, Z;Gille, A;Offermanns, S
烟酸（烟酸）长期以来一直被用作抗血脂异常药物。其特殊的作用，特别是烟酸诱导的HDL-胆固醇水平升高，在目前治疗脂质紊乱的药理学工具中是独一无二的。最近，G蛋白偶联受体，称为GPR 109 A（HM 74 A在人类，PUMA-G在小鼠），被描述和显示介导的烟酸诱导的抗脂肪分解作用的脂肪细胞。烟酸的药物治疗用途的主要问题之一是强烈的潮红反应。这种副作用虽然无害，但会严重影响患者的依从性。在本研究中，我们表明，缺乏PUMA-G的小鼠没有表现出烟酸诱导的潮红。此外，在缺乏1型环氧合酶的情况下，烟酸引起的潮红也被消除，缺乏前列腺素D-2（PGD（2））和前列腺素E-2（PGE（2））受体的小鼠潮红反应减少。GPR 109 A的小鼠直系同源物PUMA-G在巨噬细胞和其他免疫细胞中高度表达，并且将野生型骨髓移植到受辐射的PUMA-G缺陷小鼠中恢复了烟酸诱导的潮红反应。我们的数据清楚地表明，GPR 109 A介导烟酸诱导的潮红，这种作用涉及PGE（2）和PGD（2）的释放，最有可能来自皮肤的免疫细胞。
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.