DEFECTIVE REMOVAL OF CELLULAR CHOLESTEROL AND PHOSPHOLIPIDS BY APOLIPOPROTEIN-A-I IN TANGIER DISEASE
DEFECTIVE REMOVAL OF CELLULAR CHOLESTEROL AND PHOSPHOLIPIDS BY APOLIPOPROTEIN-A-I IN TANGIER DISEASE
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DOI：
10.1172/jci118082
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发表时间：
1995-07-01
影响因子：
15.9
通讯作者：
ORAM, JF
中科院分区：
文献类型：
--
作者：
FRANCIS, GA;KNOPP, RH;ORAM, JF
丹吉尔病是一种罕见的遗传性疾病，其特征是血浆中高密度脂蛋白和载脂蛋白a - 1水平极低，组织中胆固醇酯沉积，心血管疾病患病率高。我们研究了高密度脂蛋白载脂蛋白介导的细胞脂质去除在丹吉尔病中可能存在缺陷的可能性。用正常受试者的成纤维细胞，纯化的载脂蛋白A-I清除了细胞中的胆固醇酯，耗尽了细胞中可用于酯化的游离胆固醇池，并刺激了放射性标记胆固醇、磷脂酰胆碱和鞘磷脂的外排。然而，对于来自两个不相干的丹吉尔患者的成纤维细胞，载脂蛋白A-I对这些脂质转运过程的影响很小或没有影响。完整的高密度脂蛋白也不能清除丹吉尔细胞中的胆固醇酯，即使它能将放射性标记的胆固醇排出到正常水平的50-70%。丹吉尔细胞将放射性标记的胆固醇或磷脂被动解吸到含有白蛋白或胰蛋白酶化高密度脂蛋白的培养基中是正常的。结合研究表明载脂蛋白A-I与丹吉尔成纤维细胞上高亲和力结合位点的相互作用是异常的。这些结果表明载脂蛋白a - i从丹吉尔成纤维细胞中去除胆固醇和磷脂的能力受损，可能是因为载脂蛋白a - i与细胞表面结合位点的相互作用存在缺陷。载脂蛋白A-I获取细胞脂质失败可能是丹吉尔病中新生HDL颗粒快速分解代谢和血浆HDL水平低的原因。
Tangier disease is a rare genetic disorder characterized by extremely low plasma levels of HDL and apo A-I, deposition of cholesteryl esters in tissues, and a high prevalence of cardiovascular disease. We examined the possibility that HDL apolipoprotein-mediated removal of cellular lipids may be defective in Tangier disease. With fibroblasts from normal subjects, purified apo A-I cleared cells of cholesteryl esters, depleted cellular free cholesterol pools available for esterification, and stimulated efflux of radiolabeled cholesterol, phosphatidylcholine and sphingomyelin. With fibroblasts from two unrelated Tangier patients, however, apo A-I had little or no effect on any of these lipid transport processes. Intact HDL also was unable to clear cholesteryl esters from Tangier cells even though it promoted radiolabeled cholesterol efflux to levels 50-70% normal. Passive desorption of radiolabeled cholesterol or phospholipids into medium containing albumin or trypsinized HDL was normal for Tangier cells. Binding studies showed that the interaction of apo A-I with high-affinity binding sites on Tangier fibroblasts was abnormal. These results indicate that apo A-I has an impaired ability to remove cholesterol and phospholipid from Tangier fibroblasts, possibly because of a defective interaction of apo A-I with cell-surface binding sites. Failure of apo A-I to acquire cellular lipids may account for the rapid catabolism of nascent HDL particles and the low plasma HDL levels in Tangier disease.