Francis G A, Knopp R H, Oram J F
Department of Medicine, University of Washington, Seattle 98195, USA.
J Clin Invest. 1995 Jul;96(1):78-87. doi: 10.1172/JCI118082.
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.
丹吉尔病是一种罕见的遗传性疾病，其特征为血浆高密度脂蛋白（HDL）和载脂蛋白A-I（apo A-I）水平极低、胆固醇酯在组织中沉积以及心血管疾病的高患病率。我们研究了在丹吉尔病中HDL载脂蛋白介导的细胞脂质清除可能存在缺陷的可能性。对于来自正常受试者的成纤维细胞，纯化的apo A-I可清除细胞内的胆固醇酯，耗尽可用于酯化的细胞游离胆固醇池，并刺激放射性标记的胆固醇、磷脂酰胆碱和鞘磷脂的流出。然而，对于来自两名无关的丹吉尔病患者的成纤维细胞，apo A-I对这些脂质转运过程中的任何一个几乎没有影响。完整的HDL也无法从丹吉尔细胞中清除胆固醇酯，尽管它能将放射性标记的胆固醇流出促进至正常水平的50 - 70%。对于丹吉尔细胞，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处理的HDL的培养基中是正常的。结合研究表明，apo A-I与丹吉尔病成纤维细胞上高亲和力结合位点的相互作用异常。这些结果表明，apo A-I从丹吉尔病成纤维细胞中清除胆固醇和磷脂的能力受损，这可能是由于apo A-I与细胞表面结合位点的相互作用存在缺陷。apo A-I无法获取细胞脂质可能解释了丹吉尔病中新生HDL颗粒的快速分解代谢和低血浆HDL水平。
