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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2295.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Ruud Out; Menno Hoekstra; Reeni B. Hildebrand; Janine K. Kruit; Illiana Meurs; Zhaosha Li; Folkert Kuipers; Theo J.C. Van Berkel; Miranda Van Eck

From the Division of Biopharmaceutics (R.O., M.H., R.B.H., I.M., Z.L., T.J.C.V.B., M.V.E.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands; From the Center for Liver, Digestive and Metabolic Diseases (J.K., F.K.), Laboratory of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands.

Correspondence to R. Out, Division of Biopharmaceutics, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, The Netherlands. E-mail r.out{at}lacdr.leidenuniv.nl

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±12x10³ µm² for ABCG1^+/+ LDLr^–/– mice versus 65±15x10³ µm² for ABCG1^–/– LDLr^–/– mice and after 12 weeks of high-cholesterol diet feeding 124±17x10³ µm² for ABCG1^+/+ LDLr^–/– mice versus 168±17x10³ µm² for ABCG1^–/– LDLr^–/– mice. Atherosclerotic lesion size depended on both time and the macrophage ABCG1 genotype (P=0.038 by 2-way ANOVA, n8), 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.

To assess the role of macrophage ABCG1 in atherosclerosis, we generated LDL receptor knockout mice that are selectively deficient in macrophage ABCG1 by using bone marrow transfer. Feeding the mice a high-cholesterol diet led to heavy lipid accumulation in macrophages of the lung, and moderately influenced atherosclerotic lesion development.

Key Words: ABCG1 • atherosclerosis • cholesterol • macrophage • transplantation

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Is Two out of Three Enough for ABCG1?

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