Wang Nan, Ranalletta Mollie, Matsuura Fumihiko, Peng Felix, Tall Alan R
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA.
Arterioscler Thromb Vasc Biol. 2006 Jun;26(6):1310-6. doi: 10.1161/01.ATV.0000218998.75963.02. Epub 2006 Mar 23.
This study examines the ABCG1-mediated cholesterol efflux and intracellular cholesterol transport by studying the ABCG1 localization and function in macrophages.
HEK 293 cell overexpressing ABCG1, RNA interference, or macrophages from ABCG1 or ABCG4 knockout mice were used. ABCG1 but not ABCG4 had a major role in the increased cholesterol mass efflux produced by treatment of macrophages with LXR activators. In 293 cells, ABCG1 was found in the plasma membrane, Golgi, and recycling endosomes. In contrast, in basal macrophages, ABCG1 was predominantly intracellular, and redistributed to the plasma membrane after LXR activation. LXR activation increased macrophage cholesterol efflux to high-density lipoprotein (HDL), low-density lipoprotein (LDL), and cyclodextrin in an ABCG1-dependent fashion. Suppression of ABCG1 expression increased cholesteryl ester formation and decreased SREBP2 target gene expression in macrophages, even in the absence of HDL acceptors.
LXR activation induces redistribution of ABCG1 from intracellular sites to the plasma membrane and increases cholesterol mass efflux to HDL in an ABCG1-dependent fashion. ABCG1 acts in the macrophage plasma membrane to increase the availability of cholesterol to a variety of lipoprotein and nonlipoprotein acceptors while limiting the accumulation of cholesterol in the endoplasmic reticulum.
本研究通过研究ABCG1在巨噬细胞中的定位和功能，来检测ABCG1介导的胆固醇流出和细胞内胆固醇转运。
使用过表达ABCG1的HEK 293细胞、RNA干扰技术，或来自ABCG1或ABCG4基因敲除小鼠的巨噬细胞。ABCG1而非ABCG4在用LXR激活剂处理巨噬细胞所产生的胆固醇大量流出中起主要作用。在293细胞中，ABCG1存在于质膜、高尔基体和再循环内体中。相比之下，在基础状态的巨噬细胞中，ABCG1主要位于细胞内，在LXR激活后重新分布到质膜。LXR激活以ABCG1依赖的方式增加巨噬细胞向高密度脂蛋白（HDL）、低密度脂蛋白（LDL）和环糊精的胆固醇流出。抑制ABCG1表达会增加巨噬细胞中胆固醇酯的形成，并降低SREBP2靶基因的表达，即使在没有HDL受体的情况下也是如此。
LXR激活诱导ABCG1从细胞内位点重新分布到质膜，并以ABCG1依赖的方式增加向HDL的胆固醇大量流出。ABCG1在巨噬细胞质膜中发挥作用，增加胆固醇对多种脂蛋白和非脂蛋白受体的可用性，同时限制胆固醇在内质网中的积累。
