Goldiner Ilana, van der Velde Astrid E, Vandenberghe Kristin E, van Wijland Michel A, Halpern Zamir, Gilat Tuvia, Konikoff Fred M, Veldman Robert Jan, Groen Albert K
AMC Liver Centre, Academic Medical Centre, Amsterdam, The Netherlands.
Biochem J. 2006 Jun 15;396(3):529-36. doi: 10.1042/BJ20051694.
FABACs (fatty acid-bile acid conjugates) are synthetic molecules that are designed to treat a range of lipid disorders. The compounds prevent cholesterol gallstone formation and diet-induced fatty liver, and increase reverse cholesterol transport in rodents. The aim of the present study was to investigate the effect of FABACs on cholesterol efflux in human cells. Aramchol (3beta-arachidylamido-7alpha,12alpha,5beta-cholan-24-oic acid) increased cholesterol efflux from human skin fibroblasts in a dose-dependent manner in the absence of known efflux mediators such as apoA-I (apolipoprotein A-I), but had little effect on phospholipid efflux. An LXR (liver X receptor) agonist strongly increased Aramchol-induced cholesterol efflux; however, in ABCA1 (ATP-binding cassette transporter A1)-deficient cells from Tangier disease patients, the Aramchol effect was absent, indicating that activity of ABCA1 was required. Aramchol did not affect ABCA1 expression, but plasma membrane levels of the transporter increased 2-fold. Aramchol is the first small molecule that induces ABCA1-dependent cholesterol efflux without affecting transcriptional control. These findings may explain the beneficial effect of the compound on atherosclerosis.
脂肪酸 - 胆汁酸共轭物（FABACs）是一类合成分子，旨在治疗一系列脂质紊乱疾病。这些化合物可预防胆固醇胆结石的形成和饮食诱导的脂肪肝，并增加啮齿动物体内的胆固醇逆向转运。本研究的目的是探究FABACs对人体细胞中胆固醇流出的影响。在不存在诸如载脂蛋白A-I（apoA-I）等已知流出介质的情况下，阿瑞莫可（3β-花生四烯酰胺基-7α,12α,5β-胆烷-24-酸）以剂量依赖性方式增加了人体皮肤成纤维细胞中的胆固醇流出，但对磷脂流出影响甚微。一种肝脏X受体（LXR）激动剂可显著增强阿瑞莫可诱导的胆固醇流出；然而，在患有丹吉尔病患者的ATP结合盒转运体A1（ABCA1）缺陷细胞中，阿瑞莫可没有效果，这表明ABCA1的活性是必需的。阿瑞莫可不影响ABCA1的表达，但该转运体的质膜水平增加了2倍。阿瑞莫可是首个不影响转录调控而诱导ABCA1依赖性胆固醇流出的小分子。这些发现可能解释了该化合物对动脉粥样硬化的有益作用。
