Macrophage ABCG1 Deletion Disrupts Lipid Homeostasis in Alveolar Macrophages and Moderately Influences Atherosclerotic Lesion Development in LDL Receptor-Deficient Mice

OBJECTIVE—ABCG1 has recently been identified as a facilitator of cellular cholesterol and phospholipid efflux to high-density lipoprotein (HDL). Its expression in macrophages is induced during cholesterol uptake in macrophages and by liver X receptor (LXR). The role of macrophage ABCG1 in atherosclerotic lesion development is, however, still unknown. METHODS AND RESULTS—To assess the role of macrophage ABCG1 in atherosclerosis, we generated low-density lipoprotein (LDL) receptor knockout (LDLr) mice that are selectively deficient in macrophage ABCG1 by using bone marrow transfer (ABCG1 → LDLr). Peritoneal macrophages isolated from donor ABCG1 mice exhibited a 22% (P=0.0007) decrease in cholesterol efflux to HDL. To induce atherosclerosis, transplanted mice were fed a high-cholesterol diet containing 0.25% cholesterol and 15% fat for 6 and 12 weeks. Serum lipid levels and lipoprotein profiles did not differ significantly between ABCG1 → LDLr mice and controls. In lungs of ABCG1 → LDLr mice a striking accumulation of lipids was observed in macrophages localized to the subpleural region. After 6 weeks of high-cholesterol diet feeding the atherosclerotic lesion size was 49±12×10 μm for ABCG1 → LDLr mice versus 65±15×10 μm for ABCG1 → LDLr mice and after 12 weeks of high-cholesterol diet feeding 124±17×10 μm for ABCG1 → LDLr mice versus 168±17×10 μm for ABCG1 → LDLr mice. Atherosclerotic lesion size depended on both time and the macrophage ABCG1 genotype (P=0.038 by 2-way ANOVA, n≥8), indicating a moderately 33% to 36% increase in lesion formation in the absence of macrophage ABCG1. CONCLUSIONS—Macrophage ABCG1 deficiency does lead to heavy lipid accumulation in macrophages of the lung, and also a moderately significant effect on atherosclerotic lesion development was observed.