ABCG1 (ABC8), the human homolog of the Drosophila White gene, is a regulator of macrophage cholesterol and phospholipid transport

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 efflux 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 (ABQ 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. immunocyto- chemical and flow cytometric analyses revealed that ABCG1 is ex- pressed on the cell surface and in intracellular compartments of choIesterol-laden macrophages. inhibition of ABCG1 protein expres- sion 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-medi- ated lipid release, suggesting a potential function for these trans- porters 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 macro- phages