Attie A D, Kastelein J P, Hayden M R
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
J Lipid Res. 2001 Nov;42(11):1717-26.
The identification of mutations in ABCA1 in patients with Tangier disease and familial HDL deficiency demonstrated that inadequate transport of phospholipid and cholesterol to the extracellular space results in the hypercatabolism of lipid-poor nascent HDL particles. However, the relationship between changes in ABCA1 activity and HDL levels is not clear. To address this question directly in vivo, we have used bacterial artificial chromosome transgenic approaches, which allow for appropriate developmental and cellular localization of human ABCA1 in mouse tissues. Increased expression of ABCA1 is directly associated with an increase in HDL levels, and the relationship between the increase in efflux and HDL is completely linear (r2 = 0.87). Preliminary data have suggested that coronary artery disease (CAD) is increased in heterozygotes for ABCA1 deficiency. These results may have been biased by clinical sampling, and CAD end points are insensitive markers. We have now used surrogate end points of intima-media complex thickness (IMT) and have shown that mean IMT in ABCA1 heterozygotes is indeed increased. A strong correlation between adjusted IMT and HDL cholesterol values and apolipoprotein A-I-driven efflux has been established. These studies suggest that compromised ABCA1 activity leads to accelerated and early atherogenesis and provides a link between the cholesterol deposition in macrophages within the arterial wall and cholesterol efflux in humans.
对丹吉尔病和家族性高密度脂蛋白缺乏症患者ABCA1基因突变的鉴定表明，磷脂和胆固醇向细胞外空间的转运不足导致新生的低脂高密度脂蛋白颗粒的分解代谢增加。然而，ABCA1活性变化与高密度脂蛋白水平之间的关系尚不清楚。为了在体内直接解决这个问题，我们使用了细菌人工染色体转基因方法，该方法能够使人ABCA1在小鼠组织中进行适当的发育和细胞定位。ABCA1表达增加与高密度脂蛋白水平升高直接相关，流出增加与高密度脂蛋白之间的关系完全呈线性（r2 = 0.87）。初步数据表明，ABCA1缺乏症杂合子患冠状动脉疾病（CAD）的风险增加。这些结果可能受到临床抽样的影响，而且CAD终点是不敏感的标志物。我们现在使用内膜-中膜复合体厚度（IMT）作为替代终点，并表明ABCA1杂合子的平均IMT确实增加。已确定调整后的IMT与高密度脂蛋白胆固醇值以及载脂蛋白A-I驱动的流出之间存在强相关性。这些研究表明，ABCA1活性受损会导致动脉粥样硬化加速和早期发生，并在动脉壁内巨噬细胞中的胆固醇沉积与人体胆固醇流出之间建立了联系。
