Dove Dwayne E, Su Yan Ru, Zhang Wenwu, Jerome W Gray, Swift Larry L, Linton MacRae F, Fazio Sergio
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tenn 37232-6300, USA.
Arterioscler Thromb Vasc Biol. 2005 Jan;25(1):128-34. doi: 10.1161/01.ATV.0000148323.94021.e5. Epub 2004 Oct 21.
Acyl-coenzyme A: cholesterol acyltransferase (ACAT) converts intracellular free cholesterol (FC) into cholesteryl esters (CE) for storage in lipid droplets. Recent studies in our laboratory have shown that the deletion of the macrophage ACAT1 gene results in apoptosis and increased atherosclerotic lesion area in the aortas of hyperlipidemic mice. The objective of the current study was to elucidate the mechanism of the increased atherosclerosis.
CE storage and FC efflux were studied in ACAT1(-/-) peritoneal macrophages that were treated with acetylated low-density lipoprotein (acLDL). Our results show that efflux of cellular cholesterol was reduced by 25% in ACAT1-deficient cells compared with wild-type controls. This decrease occurred despite the upregulated expression of ABCA1, an important mediator of cholesterol efflux. In contrast, ACAT1 deficiency increased efflux of the cholesterol derived from acLDL by 32%. ACAT1-deficient macrophages also showed a 26% increase in the accumulation of FC derived from acLDL, which was associated with a 75% increase in the number of intracellular vesicles.
Together, these data show that macrophage ACAT1 influences the efflux of both cellular and lipoprotein-derived cholesterol and propose a pathway for the pro-atherogenic transformation of ACAT1(-/-) macrophages.
酰基辅酶A：胆固醇酰基转移酶（ACAT）将细胞内游离胆固醇（FC）转化为胆固醇酯（CE），以储存于脂滴中。我们实验室最近的研究表明，巨噬细胞ACAT1基因的缺失会导致高脂血症小鼠主动脉凋亡并增加动脉粥样硬化病变面积。本研究的目的是阐明动脉粥样硬化加重的机制。
在经乙酰化低密度脂蛋白（acLDL）处理的ACAT1（-/-）腹膜巨噬细胞中研究CE储存和FC流出。我们的结果显示，与野生型对照相比，ACAT1缺陷细胞中细胞胆固醇流出减少了25%。尽管胆固醇流出的重要介质ABCA1表达上调，但仍出现了这种减少。相比之下，ACAT1缺陷使源自acLDL的胆固醇流出增加了32%。ACAT1缺陷的巨噬细胞还显示，源自acLDL的FC积累增加了26%，这与细胞内囊泡数量增加75%有关。
总之，这些数据表明巨噬细胞ACAT1影响细胞源性和脂蛋白源性胆固醇的流出，并提出了ACAT1（-/-）巨噬细胞促动脉粥样硬化转变的途径。
