(D)-β-hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G
(D)-β-hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G
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DOI：
10.1074/jbc.c500213200
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发表时间：
2005-07-22
影响因子：
4.8
通讯作者：
Waters, MG
中科院分区：
文献类型：
--
作者：
Taggart, AKP;Kero, J;Waters, MG
作为一种治疗血脂异常的方法，每天口服1-3克烟酸可以降低血清甘油三酯，提高高密度脂蛋白胆固醇，降低冠心病的死亡率(Tavintharan， S., and Kashyap， M. L. (2001) Curr。Atheroscler。众议员3,74 -82)。这些益处可能是由于烟酸能够抑制脂肪细胞的脂肪分解，从而降低血清非酯化脂肪酸水平（Carlson, l.a. (1963) Acta Med. Scand. 173, 719-722）。在小鼠中，烟酸通过PUMA-G抑制脂肪分解，PUMA-G是一种G（i/o）偶联的7 -跨膜受体，在脂肪细胞和活化的巨噬细胞中表达（Tunaru， S., Kero， J., Schaub, a ., Wufka， C., Blaukat, a ., Pfeffer， K.，和Offermanns， S.（2003）中华医学杂志，9,352-355）。人类同源物HM74a也是一种烟酸受体，可能在抗脂肪分解中具有类似的作用。内源性烟酸水平太低，不会显著影响受体活性，因此HM74a/PUMA-G的天然配体仍有待阐明。在这里，我们发现脂肪酸衍生酮体(D)- β -羟基丁酸酯（(D)- β - ohb）特异性激活空腹期间血清中观察到的浓度的PUMA-G/HM74a。与烟酸一样，(D)- β - ohb以puma - g依赖的方式抑制小鼠脂肪细胞脂解，因此是该孤儿受体的第一个内源性配体。这些发现表明，(D)- β - ohb负调控其自身的产生，从而防止酮症酸中毒，促进脂肪储存的有效利用，这是饥饿存活的稳态机制。
As a treatment for dyslipidemia, oral doses of 1-3 grams of nicotinic acid per day lower serum triglycerides, raise high density lipoprotein cholesterol, and reduce mortality from coronary heart disease (Tavintharan, S., and Kashyap, M. L. (2001) Curr. Atheroscler. Rep. 3, 74-82). These benefits likely result from the ability of nicotinic acid to inhibit lipolysis in adipocytes and thereby reduce serum non-esterified fatty acid levels (Carlson, L. A. (1963) Acta Med. Scand. 173, 719-722). In mice, nicotinic acid inhibits lipolysis via PUMA-G, a G(i/o)-coupled seven-transmembrane receptor expressed in adipocytes and activated macrophages (Tunaru, S., Kero, J., Schaub, A., Wufka, C., Blaukat, A., Pfeffer, K., and Offermanns, S. (2003) Nat. Med. 9, 352-355). The human ortholog HM74a is also a nicotinic acid receptor and likely has a similar role in anti-lipolysis. Endogenous levels of nicotinic acid are too low to significantly impact receptor activity, hence the natural ligands(s) of HM74a/PUMA-G remain to be elucidated. Here we show that the fatty acid-derived ketone body (D)-beta-hydroxybutyrate ((D)-beta-OHB) specifically activates PUMA-G/HM74a at concentrations observed in serum during fasting. Like nicotinic acid, (D)-beta-OHB inhibits mouse adipocyte lipolysis in a PUMA-G-dependent manner and is thus the first endogenous ligand described for this orphan receptor. These findings suggests a homeostatic mechanism for surviving starvation in which (D)-beta-OHB negatively regulates its own production, thereby preventing ketoacidosis and promoting efficient use of fat stores.