Genetic deletion of low density lipoprotein receptor impairs sterol-induced mouse macrophage ABCA1 expression: A new SREBP1-dependent mechanism

Low density lipoprotein receptor (LDLR) mutations cause familial hypercholesterolemia and early atherosclerosis. ABCA1 facilitates free cholesterol efflux from peripheral tissues. We investigated the effects of LDLR deletion (LDLR^-/-) on ABCA1 expression. LDLR^-/- macrophages had reduced basal levels of ABCA1, ABCG1, and cholesterol efflux. A high fat diet increased cholesterol in LDLR^-/- macrophages but not wild type cells. A liver X receptor (LXR) agonist induced expression of ABCA1, ABCG1, and cholesterol efflux in both LDLR^-/- and wild type macrophages, whereas expression of LXRα or LXRβ was similar. Interestingly, oxidized LDL induced more ABCA1 in wild type macrophages than LDLR^-/- cells. LDL induced ABCA1 expression in wild type cells but inhibited it in LDLR^-/- macrophages in a concentration-dependent manner. However, lipoproteins regulated ABCG1 expression similarly in LDLR ^-/- and wild type macrophages. Cholesterol or oxysterols induced ABCA1 expression in wild type macrophages but had little or inhibitory effects on ABCA1 expression in LDLR^-/- macrophages. Active sterol regulatory element-binding protein 1a (SREBP1a) inhibited ABCA1 promoter activity in an LXRE-dependent manner and decreased both macrophage ABCA1 expression and cholesterol efflux. Expression of ABCA1 in animal tissues was inversely correlated to active SREBP1. Oxysterols inactivated SREBP1 in wild type macrophages but not in LDLR^-/- cells. Oxysterol synergized with non-steroid LXR ligand induced ABCA1 expression in wild type macrophages but blocked induction in LDLR^-/- cells. Taken together, our studies suggest that LDLR is critical in the regulation of cholesterol efflux and ABCA1 expression in macrophage. Lack of the LDLR impairs sterol-induced macrophage ABCA1 expression by a sterol regulatory element-binding protein 1-dependent mechanism that can result in reduced cholesterol efflux and lipid accumulation in macrophages under hypercholesterolemic conditions.