LXR-induced redistribution of ABCG1 to plasma membrane in macrophages enhances cholesterol mass efflux to HDL

Objectives-This study examines the ABCG1-mediated cholesterol efflux and intracellular cholesterol transport by studying the ABCG1 localization and function in macrophages. Methods and Results-HEK 293 cell overexpressing ABCG1, RNA interference, or macrophages from ABCG1 or ABCG4 knockout mice were used. ABCG1 but not ABCG4 had a major role in the increased cholesterol mass efflux produced by treatment of macrophages with LXR activators. In 293 cells, ABCG1 was found in the plasma membrane, Golgi, and recycling endosomes. In contrast, in basal macrophages, ABCG1 was predominantly intracellular, and redistributed to the plasma membrane after LXR activation. LXR activation increased macrophage cholesterol efflux to high-density lipoprotein (HDL), low-density lipoprotein (LDL), and cyclodextrin in an ABCG1-dependent fashion. Suppression of ABCG1 expression increased cholesteryl ester formation and decreased SREBP2 target gene expression in macrophages, even in the absence of HDL acceptors. Conclusions-LXR activation induces redistribution of ABCG1 from intracellular sites to the plasma membrane and increases cholesterol mass efflux to HDL in an ABCG1-dependent fashion. ABCG1 acts in the macrophage plasma membrane to increase the availability of cholesterol to a variety of lipoprotein and nonlipoprotein acceptors while limiting the accumulation of cholesterol in the endoplasmic reticulum.