Reduced ABCA1-mediated cholesterol efflux and accelerated atherosclerosis in apolipoprotein E-deficient mice lacking macrophage-derived ACAT1
Reduced ABCA1-mediated cholesterol efflux and accelerated atherosclerosis in apolipoprotein E-deficient mice lacking macrophage-derived ACAT1
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DOI：
10.1161/01.cir.0000164236.19860.13
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发表时间：
2005-05-10
期刊：
影响因子：
37.8
通讯作者：
Fazio, S
中科院分区：
文献类型：
--
作者：
Su, YR;Dove, DE;Fazio, S
背景-巨噬细胞酰基辅酶A：胆固醇酰基转移酶1（ACAT 1）和载脂蛋白E（apoE）参与调节细胞胆固醇稳态，因此在泡沫细胞形成中起关键作用。ACAT 1或apoE的缺失导致高脂血症小鼠动脉粥样硬化增加，可能是胆固醇加工改变的结果。我们研究了巨噬细胞ACAT 1缺失对apoE缺陷型大鼠动脉粥样硬化形成的影响。方法和结果-我们使用骨髓移植产生具有4种基因型巨噬细胞的apoE（-/-）小鼠：apoE（+/+）/ACAT 1（+/+）（野生型）、apoE（+/+）/ACAT 1（-/-）（ACAT（-/-））、apoE（-/-）/ACAT 1（+/+）（apoE（-/-））和apoE（-/-）/ACAT 1（-/-）（2KO）。当巨噬细胞apoE存在时，血浆胆固醇水平正常化，ACAT 1缺乏对动脉粥样硬化形成没有显著影响。然而，当巨噬细胞apoE不存在时，ACAT 1缺陷增加了近端主动脉的动脉粥样硬化和细胞凋亡。与ACAT 1（+/+）对照组相比，ACAT 1（-/-）腹腔巨噬细胞中胆固醇向apoA-I的流出显著减少（30%至40%; P < 0.001），无论apoE表达如何。相对于ACAT 1（+/+）巨噬细胞，2KO巨噬细胞的ABCA 1信息水平增加3至4倍，但ABCA 1蛋白水平降低。ACAT 1（-/-）巨噬细胞的微阵列分析表明，增加促炎和前胶原基因和减少基因调节膜的完整性，蛋白质的生物合成，和apoptosis. Conclusions-缺乏巨噬细胞ACAT 1加速动脉粥样硬化在hypercholesterolemic apoE（-/-）小鼠，但没有影响时，高胆固醇血症是纠正巨噬细胞apoE表达。然而，ACAT 1缺失损害ABCA 1介导的巨噬细胞中的胆固醇流出，无论载脂蛋白E的表达。膜稳定性、细胞凋亡敏感性和炎症反应的变化在此过程中可能也很重要。
Background-Macrophage acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) and apolipoprotein E (apoE) have been implicated in regulating cellular cholesterol homeostasis and therefore play critical roles in foam cell formation. Deletion of either ACAT1 or apoE results in increased atherosclerosis in hyperlipidemic mice, possibly as a consequence of altered cholesterol processing. We have studied the effect of macrophage ACAT1 deletion on atherogenesis in apoE-deficient (apoE(-/-)) mice with or without the restoration of macrophage apoE.Methods and Results-We used bone marrow transplantation to generate apoE(-/-) mice with macrophages of 4 genotypes: apoE(+/+)/ACAT1(+/+) (wild type), apoE(+/+)/ACAT1(-/-) (ACAT(-/-)), apoE(-/-)/ACAT1(+/+) (apoE(-/-)), and apoE(-/-)/ACAT1(-/-) (2KO). When macrophage apoE was present, plasma cholesterol levels normalized, and ACAT1 deficiency did not have significant effects on atherogenesis. However, when macrophage apoE was absent, ACAT1 deficiency increased atherosclerosis and apoptosis in the proximal aorta. Cholesterol efflux to apoA-I was significantly reduced (30% to 40%; P < 0.001) in ACAT1(-/-) peritoneal macrophages compared with ACAT1(+/+) controls regardless of apoE expression. 2KO macrophages had a 3- to 4-fold increase in ABCA1 message levels but decreased ABCA1 protein levels relative to ACAT1(+/+) macrophages. Microarray analyses of ACAT1(-/-) macrophages showed increases in proinflammatory and procollagen genes and decreases in genes regulating membrane integrity, protein biosynthesis, and apoptosis.Conclusions-Deficiency of macrophage ACAT1 accelerates atherosclerosis in hypercholesterolemic apoE(-/-) mice but has no effect when the hypercholesterolemia is corrected by macrophage apoE expression. However, ACAT1 deletion impairs ABCA1-mediated cholesterol efflux in macrophages regardless of apoE expression. Changes in membrane stability, susceptibility to apoptosis, and inflammatory response may also be important in this process.