Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice
Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice
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DOI：
10.1172/jci33372
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发表时间：
2007-12-01
影响因子：
15.9
通讯作者：
Tall, Alan R.
中科院分区：
文献类型：
--
作者：
Yvan-Charvet, Laurent;Ranalletta, Mollie;Tall, Alan R.
高密度脂蛋白可防止动脉粥样硬化的发展，但其潜在机制尚不清楚。HDL及其载脂蛋白可通过ATP结合盒转运体ABCA 1和ABCG 1促进胆固醇从巨噬泡沫细胞流出。针对ABCA 1和ABCG 1在动脉粥样硬化发展中的个体作用的实验产生了混合的结果，可能是因为个体KO模型中的补偿性上调。为了阐明转运蛋白介导的固醇流出在这种疾病过程中的作用，我们将Abca 1（-/-）Abcg 1（-/-）小鼠的BM移植到LDL受体缺陷小鼠中，并给予高胆固醇饮食。与对照组和单基因敲除骨髓受体相比，Abca 1（-/-）Abcg 1（-/-）骨髓受体显示动脉粥样硬化加速，巨噬细胞泡沫细胞广泛浸润心肌和脾脏。在分离的巨噬细胞的实验中，ABCA 1和ABCG 1的联合缺乏导致胆固醇流出HDL或apoA-1受损，apoE分泌显著减少，炎性细胞因子和趋化因子分泌增加。此外，当受到游离胆固醇或氧化低密度脂蛋白负载的挑战时，这些细胞显示出细胞凋亡增加。这些结果表明，ABCA 1和ABCG 1在介导巨噬细胞固醇流出中的联合作用是HDL抗动脉粥样硬化性质的核心。
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 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.