Brunham Liam R, Singaraja Roshni R, Duong MyNgan, Timmins Jenelle M, Fievet Catherine, Bissada Nagat, Kang Martin H, Samra Amrit, Fruchart Jean-Charles, McManus Bruce, Staels Bart, Parks John S, Hayden Michael R
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):548-54. doi: 10.1161/ATVBAHA.108.182303. Epub 2009 Feb 5.
The ATP-binding cassette transporter, subfamily A, member 1 (ABCA1) plays a key role in HDL cholesterol metabolism. However, the role of ABCA1 in modulating susceptibility to atherosclerosis is controversial.
We investigated the role of ABCA1 in atherosclerosis using a combination of overexpression and selective deletion models. First, we examined the effect of transgenic overexpression of a full-length human ABCA1-containing bacterial artificial chromosome (BAC) in the presence or absence of the endogenous mouse Abca1 gene. ABCA1 overexpression in the atherosclerosis-susceptible Ldlr(-/-) background significantly reduced the development of atherosclerosis in both the presence and absence of mouse Abca1. Next, we used mice with tissue-specific inactivation of Abca1 to dissect the discrete roles of Abca1 in different tissues on susceptibility to atherosclerosis. On the Apoe(-/-) background, mice lacking hepatic Abca1 had significantly reduced HDL cholesterol and accelerated atherosclerosis, indicating that the liver is an important site at which Abca1 plays an antiatherogenic role. In contrast, mice with macrophage-specific inactivation of Abca1 on the Ldlr(-/-) background displayed no change in atherosclerotic lesion area.
These data indicate that physiological expression of Abca1 modulates the susceptibility to atherosclerosis and establish hepatic Abca1 expression as an important site of atheroprotection. In contrast, we show that selective deletion of macrophage Abca1 does not significantly modulate atherogenesis.
ATP结合盒转运蛋白A亚家族成员1（ABCA1）在高密度脂蛋白胆固醇代谢中起关键作用。然而，ABCA1在调节动脉粥样硬化易感性方面的作用存在争议。
我们使用过表达和选择性缺失模型相结合的方法研究ABCA1在动脉粥样硬化中的作用。首先，我们在存在或不存在内源性小鼠Abca1基因的情况下，检测了含全长人ABCA1的细菌人工染色体（BAC）转基因过表达的效果。在动脉粥样硬化易感的Ldlr(-/-)背景下，ABCA1过表达在存在和不存在小鼠Abca1的情况下均显著减少了动脉粥样硬化的发展。接下来，我们使用具有Abca1组织特异性失活的小鼠来剖析Abca1在不同组织中对动脉粥样硬化易感性的不同作用。在Apoe(-/-)背景下，缺乏肝脏Abca1的小鼠高密度脂蛋白胆固醇显著降低，动脉粥样硬化加速，表明肝脏是Abca1发挥抗动脉粥样硬化作用的重要部位。相比之下，在Ldlr(-/-)背景下具有巨噬细胞特异性Abca1失活的小鼠动脉粥样硬化病变面积没有变化。
这些数据表明，Abca1的生理表达调节动脉粥样硬化的易感性，并确立肝脏Abca1表达是抗动脉粥样硬化的重要部位。相比之下，我们表明巨噬细胞Abca1的选择性缺失不会显著调节动脉粥样硬化的发生。
