ABCG1 (ABC8), the human homolog of the <i>Drosophila white</i> gene, is a regulator of macrophage cholesterol and phospholipid transport

作     者：Klucken, J Büchler, C Orsó, E Kaminski, WE Porsch-Özcürümez, M Liebisch, C Kapinsky, M Diederich, W Drobnik, W Dean, M Allikmets, R Schmitz, G 

作者机构：Univ Regensburg Inst Clin Chem & Lab Med D-93042 Regensburg Germany NCI Lab Genome Divers Frederick MD 21702 USA Columbia Univ Dept Ophthalmol New York NY 10032 USA Columbia Univ Dept Pathol New York NY 10032 USA 

出 版 物：《PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA》 (美国国家科学院汇刊)

年 卷 期：2000年第97卷第2期

页      面：817-822页

核心收录：

学科分类：07[理学] 08[工学] 

主　　题：ATP结合匣式转运子/分析 ATP结合匣式转运子/遗传学 ATP结合匣式转运子/生理学 生物转运 细胞 培养的 胆固醇/代谢 果蝇蛋白质类 眼蛋白质类/遗传学 基因表达调控/药物作用 免疫组织化学 昆虫蛋白质类/遗传学 动力学 脂蛋白类 HDL/药理学 脂蛋白类 LDL/药理学 巨噬细胞/化学 巨噬细胞/药物作用 巨噬细胞/代谢 单核细胞/化学 单核细胞/药物作用 单核细胞/代谢 寡核苷酸类 反义/药理学 磷脂类/代谢 RNA 信使/遗传学 RNA 信使/代谢 组织分布 动物 女(雌)性 人类 男(雄)性 

摘      要：Excessive uptake of atherogenic lipoproteins such as modified low-density lipoprotein complexes by vascular macrophages leads to foam cell formation, a critical step in atherogenesis, Cholesterol afflux mediated by high-density lipoproteins (HDL) constitutes a protective mechanism against macrophage lipid overloading. The molecular mechanisms underlying this reverse cholesterol transport process are currently not fully understood. To identify effector proteins that are involved in macrophage lipid uptake and release, we searched for genes that are regulated during lipid influx and efflux in human macrophages using a differential display approach. We report here that the ATP-binding cassette (ABC) transporter ABCG1 (ABC8) is induced in monocyte-derived macrophages during cholesterol influx mediated by acetylated low-density lipoprotein. Conversely, lipid efflux in cholesterol-laden macrophages, mediated by the cholesterol acceptor HDL3, suppresses the expression of ABCG1, Immunocytochemical and flow cytometric analyses revealed that ABCG1 is expressed on the cell surface and in intracellular compartments of cholesterol-laden macrophages. Inhibition of ABCG1 protein expression using an antisense strategy resulted in reduced HDL3-dependent efflux of cholesterol and choline-phospholipids. In a comprehensive analysis of the expression and regulation of all currently known human ABC transporters, we identified an additional set of ABC genes whose expression is regulated by cholesterol uptake or HDL3-mediated lipid release, suggesting a potential function for these transporters in macrophage lipid homeostasis. Our results demonstrating a regulator function for ABCG1 in cholesterol and phospholipid transport define a biologic activity for ABC transporters in macrophages.