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

Jochen Klucken, Christa Büchler, Evelyn Orsó, Wolfgang E. Kaminski, Mustafa Porsch-Özcürümez, Gerhard Liebisch, Michael Kapinsky, Wendy Diederich, Wolfgang Drobnik, Michael Dean, Rando Allikmets, Gerd Schmitz*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

473 Citations (Scopus)

Abstract

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 (ABC) transporter ABCG1 (ABCS) 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.

Original languageEnglish
Pages (from-to)817-822
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number2
DOIs
Publication statusPublished - 18 Jan 2000
Externally publishedYes

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