Insight into ABCG1-mediated cholesterol efflux.

Macrophages in the arterial intima take up modified LDL and become cholesterol-ester laden foam cells, which are the primary cell type in newly formed fatty streak lesions, and which play an important role throughout lesion progression and plaque vulnerability. Macrophages can unload their excess cellular cholesterol stores via lipid efflux, the first step in the protective reverse cholesterol transport pathway. In this pathway, efflux of cellular cholesterol to extracellular acceptors, such as HDL and lipid-poor apolipoproteins, targets this cholesterol for delivery to the liver for metabolism and direct excretion into the bile. The mechanisms of cellular cholesterol efflux are the focus of intensive research, and this field was advanced greatly by the discovery of ABCA1 as the Tangier disease gene in 1999.1 Tangier disease subjects have almost no plasma HDL, and their cells have a complete deficiency in cholesterol and phospholipid efflux to apolipoprotein A-I (apoAI) and a partial defect in lipid efflux to HDL.2 Thus, it was apparent that there is more than one pathway for lipid efflux to HDL. In 2001, Schmitz and colleagues demonstrated that ABCG1, another member of the ABC gene superfamily, was upregulated by cholesterol in human macrophages, and that an ABCG1 antisense oligonucleotide that reduced ABCG1 expression also decreased lipid efflux to HDL.3 The role of ABCG1 in lipid efflux was confirmed in 2004 when Wang and colleagues and Edwards and colleagues showed that ABCG1 transfected cells had increased cholesterol efflux to HDL.4,5