CELLULAR DISORDERS IN FAMILIAL HDL DEFICIENCIES

人口研究表明，血浆高密度脂蛋白水平与冠心病风险呈负相关，表明高密度脂蛋白可以预防动脉粥样硬化。这种保护作用可能与高密度脂蛋白刺激外周细胞（尤其是动脉壁细胞）清除胆固醇的能力有关。低脂HDL载脂蛋白，如apoAI，通过一个活跃的过程从细胞中清除多余的胆固醇和磷脂，这可能解释了HDL的心脏保护作用。这一途径在丹吉尔病（TD）患者的成纤维细胞中几乎不存在。丹吉尔病是一种遗传性疾病，其特征是血浆中高密度脂蛋白水平极低，组织巨噬细胞中胆固醇酯沉积，心血管疾病高发。其他形式的家族性HDL缺乏（FHD）对相同途径的损害较轻。因此，apoAI获取细胞脂质的失败可能解释了新生HDL颗粒的快速分解代谢、低HDL水平以及TD和其他fhd中动脉粥样硬化增加的原因。使用微阵列基因表达技术，我们确定了可能的TD基因产物，称为ABC1，似乎在载脂蛋白介导的脂质去除途径中发挥关键作用。我们已经准备了必要的细胞系、cdna、抗体和用于研究该蛋白及其基因的检测方法。有了这些工具，我们将利用培养细胞表征ABC1和其他新发现的蛋白质的生物学特性，我们将利用基因操纵的小鼠模型建立ABC1在全身脂蛋白代谢和动脉粥样硬化中的作用。ABC1和相关蛋白的表征将显著推进我们对通过HDL载脂蛋白清除组织中多余胆固醇的细胞过程的理解。这些研究将有助于设计治疗方法来纠正与低血浆HDL和心脏病风险增加相关的细胞疾病。

Population studies have shown an inverse correlation between plasma HDL levels and risk for coronary heart disease, suggesting that HDL protects against atherosclerosis. This protection may be related to the ability of HDL to stimulate clearance of cholesterol from peripheral cells, particularly those of the artery wall. Lipid-poor HDL apolipoproteins such as apoAI remove excess cholesterol and phospholipids from cells by an active process that may account for the cardioprotective effects of HDL. This pathway is virtually absent in fibroblasts from subjects with Tangier disease (TD), a genetic disorder characterized by extremely low plasma levels of HDL, deposition of cholesteryl esters in tissue macrophages, and a high prevalence of cardiovascular disease. Other forms of familial HDL deficiency (FHD) have a less severe impairment of the same pathway. Thus a failure of apoAI to acquire cellular lipids may account for the rapid catabolism of nascent HDL particles, low HDL levels, and increased atherosclerosis in TD and other FHDs. Using microarray gene expression technology, we identified the probable TD gene product, called ABC1 , that appears to play a critical role in the apolipoprotein-mediated lipid removal pathway. We have prepared the necessary cell lines, cDNAs, antibodies, and assays for studying this protein and its gene. With these tools, we will characterize the biologic properties of ABC1 and other newly-discovered proteins using cultured cells, and we will establish the role of ABC1 in whole-body lipoprotein metabolism and atherogenesis using genetically-manipulated mouse models. Characterization of ABC1 and related proteins will advance significantly our understanding of cellular processes involved in clearing excess cholesterol from tissues by HDL apolipoproteins. These studies will help design therapeutic approaches for correcting cellular disorders associated with low plasma HDL and increased risk for heart disease.