ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I.

OBJECTIVE To study the acceptor specificity for human ABCG1 (hABCG1)-mediated cholesterol efflux. METHODS AND RESULTS Cells overexpressing hABCG1 were created in Chinese Hamster Ovary (CHO-K1) cells and characterized in terms of lipid composition. hABCG1 expressed in these cells formed homodimers and was mostly present intracellularly. Cholesterol efflux from hABCG1 cells to HDL2 and HDL3 was increased but not to lipid-free apolipoproteins. A range of phospholipid containing acceptors apart from high-density lipoprotein (HDL) subclasses were also efficient in mediating ABCG1-dependent export of cholesterol. Importantly, a buoyant phospholipid-containing fraction generated from incubation of lipid-free apoA-I with macrophages was nearly as efficient as HDL2. The capacity of acceptors to induce ABCG1-mediated efflux was strongly correlated with their total phospholipid content, suggesting that acceptor phospholipids drive ABCG1-mediated efflux. Most importantly, acceptors for ABCG1-mediated cholesterol export could be generated from incubation of cells with lipid-free apoA-I through the action of ABCA1 alone. CONCLUSIONS These results indicate a synergistic relationship between ABCA1 and ABCG1 in peripheral tissues, where ABCA1 lipidates any lipid-poor/free apoA-I to generate nascent or pre-beta-HDL. These particles in turn may serve as substrates for ABCG1-mediated cholesterol export.