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摘要
胆固醇的循环水平来源于内源性产生或饮食的肠吸收和胆汁胆固醇。类 1尼曼匹克C1(NPC1L1)是一种跨膜蛋白,在肠道对通过囊泡内吞内源性吸收胆固醇的促进起着关键的作用。类 1尼曼匹克C1胆固醇吸收抑制剂结合其胞外环的分子靶点,抑制甾醇的吸收而不影响其他分子的吸收。胆固醇吸收抑制剂显著降低单用或加用他汀类药物时血浆总胆固醇和低密度脂蛋白(LDL-C)等离子体水平,与低剂量的他汀类药物相关的对正经历他汀类药物相关的副作用的患者是特别重要的。IMPROVE-IT研究的最近成果,对患急性冠状动脉综合征与推荐的范围内低密度脂蛋白水平的患者,评价胆固醇吸收抑制剂的心血管效应加辛伐他汀治疗,表明进一步低密度脂蛋白的降低减少心血管事件的发生率。到目前为止,类 1尼曼匹克C1表示唯一可用于临床使用,然而,新型β-内酰胺类胆固醇吸收抑制剂衍生物的合成及其有效地抑制类 1尼曼匹克C1蛋白和降低血浆胆固醇水平的评价正在进行中。
关键词: 类 1尼曼匹克C1,胆固醇,胆固醇吸收,胆固醇吸收抑制剂,低密度脂蛋白胆固醇、心血管疾病。
Current Medicinal Chemistry
Title:Niemann-Pick C1-Like 1 (NPC1L1) Inhibition and Cardiovascular Diseases
Volume: 23 Issue: 10
Author(s): A. Pirillo, A. L. Catapano, G. D. Norata
Affiliation:
关键词: 类 1尼曼匹克C1,胆固醇,胆固醇吸收,胆固醇吸收抑制剂,低密度脂蛋白胆固醇、心血管疾病。
摘要: Circulating levels of cholesterol are derived from either endogenous production or intestinal absorption of dietary and biliary cholesterol. Niemann-Pick C1-Like 1 (NPC1L1) is a transmembrane protein that plays a key role in the intestinal absorption of cholesterol by facilitating its uptake through vesicular endocytosis. NPC1L1 is the molecular target of ezetimibe which binds its extracellular loop and inhibits sterol absorption without affecting the absorption of other molecules. Ezetimibe significantly reduces plasma levels of total and low density lipoprotein cholesterol (LDL-C) as monotherapy or when added to statins, the association with a low dose of statin is of particular interest for patients experiencing statin-related side effects. The recent results of the IMPROVE-IT study, which evaluated the cardiovascular effect of ezetimibe added to simvastatin therapy in subjects who had had an acute coronary syndrome and with LDL-C levels within the recommended range, showed that a further LDL-C lowering reduced the incidence of cardiovascular events. To date, ezetimibe represents the only inhibitor of NPC1L1 available for clinical use, however, novel aminoß- lactam ezetimibe derivatives have been synthesized and their efficacy to inhibit NPC1L1 protein and decrease plasma cholesterol levels is under evaluation.
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Cite this article as:
A. Pirillo, A. L. Catapano, G. D. Norata , Niemann-Pick C1-Like 1 (NPC1L1) Inhibition and Cardiovascular Diseases, Current Medicinal Chemistry 2016; 23 (10) . https://dx.doi.org/10.2174/0929867323666160229114111
DOI https://dx.doi.org/10.2174/0929867323666160229114111 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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