CELLULAR DISORDERS IN FAMILIAL HDL DEFICIENCIES

人群研究表明，血浆HDL水平与冠心病风险之间存在负相关性，表明HDL可预防动脉粥样硬化。 这种保护作用可能与HDL刺激外周细胞（特别是动脉壁细胞）清除胆固醇的能力有关。 贫脂HDL载脂蛋白（如apoAI）通过一种主动过程从细胞中清除过量的胆固醇和磷脂，这可能是HDL的心脏保护作用的原因。该途径在来自患有丹吉尔病（TD）的受试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，其特征在于极低的HDL血浆水平、胆固醇酯在组织巨噬细胞中的沉积以及心血管疾病的高患病率。 其他形式的家族性HDL缺乏症（FHD）对同一途径的损害不太严重。 因此，apoAI获取细胞脂质的失败可能是TD和其他FHD中新生HDL颗粒快速分解、低HDL水平和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清除途径中发挥关键作用。 我们已经准备了必要的细胞系，cDNA，抗体和分析研究这种蛋白质及其基因。 有了这些工具，我们将使用培养的细胞来表征ABC 1和其他新发现的蛋白质的生物学特性，并且我们将使用遗传操作的小鼠模型来确定ABC 1在全身脂蛋白代谢和动脉粥样硬化形成中的作用。 ABC1和相关蛋白的表征将大大推进我们对HDL载脂蛋白从组织中清除过量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，纠正与低血浆HDL和心脏病风险增加相关的细胞紊乱。

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.