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(-/-) 3 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 x 10(3) mu m(2) for ABCG1(+/+) -> LDLr-/- mice versus 65 +/- 15 x 10(3) mu m(2) for ABCG1(-/-) -> LDLr-/- mice and after 12 weeks of high-cholesterol diet feeding 124 +/- 17 x 10(3) mu m(2) for ABCG1(+/+) -> LDLr-/- mice versus 168 +/- 17x10(3) mu m(2) 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.