Tunaru Sorin, Kero Jukka, Schaub Annette, Wufka Christian, Blaukat Andree, Pfeffer Klaus, Offermanns Stefan
Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany.
Nat Med. 2003 Mar;9(3):352-5. doi: 10.1038/nm824. Epub 2003 Feb 3.
Nicotinic acid (niacin), a vitamin of the B complex, has been used for almost 50 years as a lipid-lowering drug. The pharmacological effect of nicotinic acid requires doses that are much higher than those provided by a normal diet. Its primary action is to decrease lipolysis in adipose tissue by inhibiting hormone-sensitive triglyceride lipase. This anti-lipolytic effect of nicotinic acid involves the inhibition of cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue through a G(i)-protein-mediated inhibition of adenylyl cyclase. A G-protein-coupled receptor for nicotinic acid has been proposed in adipocytes. Here, we show that the orphan G-protein-coupled receptor, 'protein upregulated in macrophages by interferon-gamma' (mouse PUMA-G, human HM74), 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.
烟酸（尼克酸）是B族维生素之一，作为一种降脂药物已被使用了近50年。烟酸的药理作用所需剂量远高于正常饮食所提供的剂量。其主要作用是通过抑制激素敏感性甘油三酯脂肪酶来减少脂肪组织中的脂肪分解。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作用来抑制脂肪组织中环磷酸腺苷（cAMP）的积累。脂肪细胞中已提出存在一种烟酸的G蛋白偶联受体。在此，我们表明孤儿G蛋白偶联受体“γ干扰素在巨噬细胞中上调的蛋白”（小鼠PUMA - G，人类HM74）在脂肪组织中高度表达，并且是烟酸受体。烟酸与PUMA - G或HM74结合会导致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降低被消除，这表明PUMA - G在体内介导了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。
