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

Excessive uptake of atherogenic lipoproteins such as modified low-density l ipoprotein complexes by vascular macrophages leads to foam cell formation, a critical step in atherogenesis, Cholesterol afflux mediated by high-densi ty lipoproteins (HDL) constitutes a protective mechanism against macrophage lipid overloading. The molecular mechanisms underlying this reverse choles terol transport process are currently not fully understood. To identify eff ector proteins that are involved in macrophage lipid uptake and release, we searched for genes that are regulated during lipid influx and efflux in hu man macrophages using a differential display approach. We report here that the ATP-binding cassette (ABC) transporter ABCG1 (ABC8) is induced in monoc yte-derived macrophages during cholesterol influx mediated by acetylated lo w-density lipoprotein. Conversely, lipid efflux in cholesterol-laden macrop hages, mediated by the cholesterol acceptor HDL3, suppresses the expression of ABCG1, Immunocytochemical and flow cytometric analyses revealed that AB CG1 is expressed on the cell surface and in intracellular compartments of c holesterol-laden macrophages. Inhibition of ABCG1 protein expression using an antisense strategy resulted in reduced HDL3-dependent efflux of choleste rol and choline-phospholipids. In a comprehensive analysis of the expressio n and regulation of all currently known human ABC transporters, we identifi ed an additional set of ABC genes whose expression is regulated by choleste rol uptake or HDL3-mediated lipid release, suggesting a potential function for these transporters in macrophage lipid homeostasis. Our results demonst rating a regulator function for ABCG1 in cholesterol and phospholipid trans port define a biologic activity for ABC transporters in macrophages.