Mechanism of action of niacin
Mechanism of action of niacin
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DOI：
10.1016/j.amjcard.2008.02.029
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发表时间：
2008-04-17
影响因子：
2.8
通讯作者：
Kashyap, Moti L.
中科院分区：
文献类型：
--
作者：
Kamanna, Vaijinath S.;Kashyap, Moti L.
烟酸（烟酸）长期以来一直用于治疗血脂紊乱和心血管疾病。烟酸有利地影响含载脂蛋白 (apo) B 的脂蛋白（例如极低密度脂蛋白 [VLDL]、低密度脂蛋白 [LDL]、脂蛋白[a]）并增加含载脂蛋白 A-I 的脂蛋白（高密度脂蛋白 [HDL]）。最近，新的发现扩大了我们对烟酸作用机制的理解，并挑战了旧的概念。有关以下方面的新数据：(1) 烟酸如何影响肝脏中甘油三酯 (TG) 和含载脂蛋白 B 的脂蛋白代谢，(2) 烟酸如何影响载脂蛋白 A-1 和 HDL 代谢，(3) 烟酸如何影响血管抗炎事件，(4) 脂肪细胞和免疫细胞中的特定烟酸受体，(5) 烟酸如何引起潮红，以及 (6) 肝脏和肠道细胞中烟酸转运系统的特征。新的研究结果表明，烟酸直接且非竞争性地抑制肝细胞二酰基甘油酰基转移酶-2（TG 合成的关键酶）。烟酸对 TG 合成的抑制导致细胞内肝 apo B 降解加速以及 VLDL 和 LDL 颗粒分泌减少。先前对人类的动力学研究和最近的体外细胞培养结果表明，烟酸主要阻碍 apo A-1（相对于 apo A-II）的肝脏分解代谢，但不阻碍清道夫受体 BI 介导的胆固醇酯。烟酸减少 HDL-apo A-I 分解代谢解释了 HDL 半衰期和脂蛋白 A-I HDL 亚组分浓度的增加，从而增强了胆固醇的反向转运。初步数据表明，烟酸通过抑制肝细胞表面β链三磷酸腺苷合酶（最近报道的HDL-apo A-I全颗粒受体）的表达，抑制HDL-apo A-1的去除。最近的研究表明，烟酸可增加血管内皮细胞的氧化还原状态，从而抑制氧化应激和血管炎症基因（参与动脉粥样硬化的关键细胞因子）。烟酸潮红是皮下朗格汉斯细胞通过 G 蛋白偶联受体 109A 烟酸受体刺激前列腺素 D-2 和 E-2 的结果。尽管通过 G 蛋白偶联受体 109A 烟酸受体减少脂肪组织中游离脂肪酸的动员已被广泛认为是烟酸降低 TG 的机制，但在生理和临床上，该途径可能只是解释烟酸脂质效应的次要因素。 (C) 2008 Elsevier Inc. 保留所有权利。
Nicotinic acid (niacin) has long been used for the treatment of lipid disorders and cardiovascular disease. Niacin favorably affects apolipoprotein (apo) B-containing lipoproteins (eg, very-low-density lipoprotein [VLDL], low-density lipoprotein [LDL], lipoprotein[a]) and increases apo A-I-containing lipoproteins (high-density lipoprotein [HDL]). Recently, new discoveries have enlarged our understanding of the mechanism of action of niacin and challenged older concepts. There are new data on (1) how niacin affects triglycerides (TGs) and apo B-containing lipoprotein metabolism in the liver, (2) how it affects apo A-1 and HDL metabolism, (3) how it affects vascular anti-inflammatory events, (4) a specific niacin receptor in adipocytes and immune cells, (5) how niacin causes flushing, and (6) the characterization of a niacin transport system in liver and intestinal cells. New findings indicate that niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase-2, a key enzyme for TG synthesis. The inhibition of TG synthesis by niacin results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Previous kinetic studies in humans and recent in vitro cell culture findings indicate that niacin retards mainly the hepatic catabolism of apo A-1 (vs apo A-II) but not scavenger receptor BI-mediated cholesterol esters. Decreased HDL-apo A-I catabolism by niacin explains the increases in HDL half-life and concentrations of lipoprotein A-I HDL subfractions, which augment reverse cholesterol transport. Initial data suggest that niacin, by inhibiting the hepatocyte surface expression of beta-chain adenosine triphosphate synthase (a recently reported HDL-apo A-I holoparticle receptor), inhibits the removal of HDL-apo A-1. Recent studies indicate that niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. The niacin flush results from the stimulation of prostaglandins D-2 and E-2 by subcutaneous Langerhans cells via the G protein-coupled receptor 109A niacin receptor. Although decreased free fatty acid mobilization from adipose tissue via the G protein-coupled receptor 109A niacin receptor has been a widely suggested mechanism of niacin to decrease TGs, physiologically and clinically, this pathway may be only a minor factor in explaining the lipid effects of niacin. (C) 2008 Elsevier Inc. All rights reserved.