PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect
PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect
复制标题
DOI：
10.1038/nm824
复制
发表时间：
2003-03-01
期刊：
影响因子：
82.9
通讯作者：
Offermanns, S
中科院分区：
文献类型：
--
作者：
Tunaru, S;Kero, J;Offermanns, S
烟酸（烟酸）是一种 B 族维生素，作为降脂药物已使用了近 50 年(1,2)。烟酸的药理作用需要比正常饮食提供的剂量高得多的剂量(3,4)。其主要作用是通过抑制激素敏感的甘油三酯脂肪酶来减少脂肪组织中的脂肪分解(5)。烟酸的这种抗脂肪分解作用涉及通过 G(i) 蛋白介导的腺苷酸环化酶抑制 (7-9) 来抑制脂肪组织中环磷酸腺苷 (cAMP) 的积累 (6)。已提出在脂肪细胞中存在一种烟酸 G 蛋白偶联受体 (10,11)。在这里，我们发现孤儿 G 蛋白偶联受体，“干扰素 γ 在巨噬细胞中上调的蛋白”（小鼠 PUMA-G，人 HM74）(12,13)，在脂肪组织中高度表达，并且是一种烟酸受体。烟酸与 PUMA-G 或 HM74 的结合导致 G(i) 介导的 cAMP 水平降低。在缺乏 PUMA-G 的小鼠中，烟酸诱导的游离脂肪酸 (FFA) 和甘油三酯血浆水平的降低被消除，表明 PUMA-G 在体内介导烟酸的抗脂肪分解和降脂作用。烟酸受体的鉴定可能有助于开发治疗血脂异常的新药。
Nicotinic acid (niacin), a vitamin of the B complex, has been used for almost 50 years as a lipid-lowering drug(1,2). The pharmacological effect of nicotinic acid requires doses that are much higher than those provided by a normal diet(3,4). Its primary action is to decrease lipolysis in adipose tissue by inhibiting hormone-sensitive triglyceride lipase(5). This anti-lipolytic effect of nicotinic acid involves the inhibition of cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue(6) through a G(i)-protein-mediated inhibition of adenylyl cyclase(7-9). A G-protein-coupled receptor for nicotinic acid has been proposed in adipocytes(10,11). Here, we show that the orphan G-protein-coupled receptor, 'protein upregulated in macrophages by interferon-gamma' (mouse PUMA-G, human HM74)(12,13), is highly expressed in adipose tissue and is a nicotinic acid receptor. Binding of nicotinic acid to PUMA-G or HM74 results in a G(i)-mediated decrease in cAMP levels. In mice lacking PUMA-G, the nicotinic acid-induced decrease in free fatty acid (FFA) and triglyceride plasma levels was abrogated, indicating that PUMA-G mediates the anti-lipolytic and lipid-lowering effects of nicotinic acid in vivo. The identification of the nicotinic acid receptor may be useful in the development of new drugs to treat dyslipidemia.