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Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice
Laurent Yvan-Charvet, … , Carrie Welch, Alan R. Tall
Laurent Yvan-Charvet, … , Carrie Welch, Alan R. Tall
Published November 8, 2007
Citation Information: J Clin Invest. 2007;117(12):3900-3908. https://doi.org/10.1172/JCI33372.
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Research Article Cardiology Article has an altmetric score of 1

Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice

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Abstract

HDLs protect against the development of atherosclerosis, but the underlying mechanisms are poorly understood. HDL and its apolipoproteins can promote cholesterol efflux from macrophage foam cells via the ATP-binding cassette transporters ABCA1 and ABCG1. Experiments addressing the individual roles of ABCA1 and ABCG1 in the development of atherosclerosis have produced mixed results, perhaps because of compensatory upregulation in the individual KO models. To clarify the role of transporter-mediated sterol efflux in this disease process, we transplanted BM from Abca1–/–Abcg1–/– mice into LDL receptor–deficient mice and administered a high-cholesterol diet. Compared with control and single-KO BM recipients, Abca1–/–Abcg1–/– BM recipients showed accelerated atherosclerosis and extensive infiltration of the myocardium and spleen with macrophage foam cells. In experiments with isolated macrophages, combined ABCA1 and ABCG1 deficiency resulted in impaired cholesterol efflux to HDL or apoA-1, profoundly decreased apoE secretion, and increased secretion of inflammatory cytokines and chemokines. In addition, these cells showed increased apoptosis when challenged with free cholesterol or oxidized LDL loading. These results suggest that the combined effects of ABCA1 and ABCG1 in mediating macrophage sterol efflux are central to the antiatherogenic properties of HDL.

Authors

Laurent Yvan-Charvet, Mollie Ranalletta, Nan Wang, Seongah Han, Naoki Terasaka, Rong Li, Carrie Welch, Alan R. Tall

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Figure 3

Cholesterol efflux from peritoneal macrophages isolated from WT, Abca1–/–, Abcg1–/–, and Abca1–/–Abcg1–/– mice.

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Cholesterol efflux from peritoneal macrophages isolated from WT, Abca1–/...
(A, B, and D) Thioglycollate-elicited macrophages were cultured for 24 h in DMEM plus 0.2% BSA containing 50 μg/ml acLDL, 3 μmol/l T0901317, and 2 μCi/ml [3H]-cholesterol. Then, a pool of human serum (2.5%; A), a pool of human serum devoid of apoB-containing particles (2.5%; B), and media devoid of acceptors or containing lipid-poor apoA-1 or apoE (D) were added as acceptor and incubated for 6 h before the media and cells were collected for analysis. (C) Cholesterol efflux was also confirmed by cholesterol mass analysis. Cells were cultured overnight with 50 μg/ml acLDL and 3 μmol/l T0901317 and then incubated for 6 hours with 50 μg/ml human HDL isolated by ultracentrifugation. The HDL-mediated net cholesterol efflux (ΔTC) was calculated as the difference of cholesterol mass of the medium with and without cells. Values are mean ± SEM. *P < 0.05 versus WT. ΧP < 0.05 versus single-KOs.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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