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Cell-biological and molecular biological analyzes of reverse cholesterol transport as a protective system against atherosclerosis

反向胆固醇转运作为动脉粥样硬化保护系统的细胞生物学和分子生物学分析

基本信息

批准号：
04404085
负责人：
MATSUZAWA Yuji
金额：
$ 20.16万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

项目摘要

I.Analysis of abnormal function of lipoproteins in cholesteryl ester transfer protein (CETP) deficiencyLipoprotein abnormalities in CETP deficiency were characterized by the presence of large and cholesteryl-ester(CE)-rich HDL and small polydisperse LDL.Large and CE-rich HDL_2 obtained from homozygous CETP-deficient subjects was less effective for reducing cholesterol content in lipid-laden macrophages than that from control subjects. The small polydisperse LDL of patients had reduced affinity for the LDL receptor of normal human fibroblasts. These abnormal in vitro function of plasma lipoproteins from CETP deficiency may be associated with athrosclerosis.II.Molecular basis of CETP deficiencyWe found that the frequency of the G-to-A mutation at the 5' splice donor slite of intron 14 in the CETP gene was approximately 1% in the Japanese general population. We also found a novel missense mutation in exon 15(D442 ; G) in markedly hyperalphalipoproteinemic patients. This novel mutation was … More revealed to be as common as the intron 14 splicing defect in Japan.III.Atherogenicity in CETP deficiencyThe hyperalphalipoproteinemic subjects with coronary heart disease (CHD) and juvenile corneal opacification (Atherosclerosis 53 ; 207-212, 1984), were identified to be homozygous for the exon 15 missense mutation. We also found that CETP-deficient patients with low HTGL may be susceptible to CHD.We found a unique area where a marked hyperalphalipoproteinemia (HALP) caused by the intron 14 splicing defect was markedly accumulated. In this area, a marked HALP and the intron 14 CETP gene mutation were less frequentry observed in the eiderly survived subjects than in the younger subjects. These results suggested that CETP deficiency may not be a longevity syndrome.IV.Lipoprotein abnormalities in primary biliary cirrhosis (PBC)PBC was known to be often associated with HALP and xanthomas.We found that plasma levels of CETP were markedly increased and HTGL activities were reduced in hyperalphalipoproteinemic patients with PBC, in contrast to CETP deficincy.V.Interaction between HDL and hepatocytes, a terminal of reverce cholesterol transportWe found that HDL is taken up and degraded by a human hepatoma cell line, Mahlavu, in contrast to extrahepatic peripheral cells, in which the degradation of HDL does not occur. The results indicated that HDL-associated cholesterol may be processed via a pathway different from that of LDL metabolism. Less

一、胆固醇酯转运蛋白（CETP）缺乏者脂蛋白功能异常的分析CETP缺乏者脂蛋白异常的特征是存在大的富含胆固醇酯（CE）的HDL和小的多分散的LDL，从纯合子CETP缺乏者获得的大的富含CE的HDL_2降低脂质巨噬细胞胆固醇含量的效果低于对照者。患者的小的多分散性LDL与正常人成纤维细胞的LDL受体的亲和力降低。这些异常的血浆脂蛋白的体外功能，从CETP缺乏症可能与atherosclerosis.II. CETP缺乏症的分子基础我们发现，在5'剪接供体狭缝的CETP基因14在日本的一般人群中的G-到-A突变的频率约为1%。我们还发现了一个新的错义突变外显子15（D442 ; G）显着高脂蛋白血症患者。这种新的突变是 ...更多信息在日本，其与内含子14剪接缺陷一样常见。III. CETP缺陷的致动脉粥样硬化性患有冠心病（CHD）和青少年角膜混浊的高脂蛋白血症受试者（Atherosclerosis 53 ; 207-212，1984）被鉴定为外显子15错义突变的纯合子。我们还发现CETP缺陷伴低HTGL的患者可能易患CHD。我们发现了一个独特的区域，由内含子14剪接缺陷引起的显著高脂蛋白血症（HALP）明显积聚。在这一区域，HALP和CETP基因内含子14突变在老年人中的发生率低于年轻人。这些结果表明，CETP缺乏可能不是一种长寿综合征。IV.原发性胆汁性肝硬化（PBC）的脂蛋白异常众所周知，原发性胆汁性肝硬化（PBC）的脂蛋白异常通常与HALP和黄色瘤有关。我们发现，与CETP缺乏相比，患有高α脂蛋白血症的PBC患者的血浆CETP水平显着升高，HTGL活性降低。V.高密度脂蛋白与肝细胞之间的相互作用，胆固醇逆向转运的末端我们发现HDL被人肝癌细胞系Mahlavu摄取并降解，而肝外外周细胞中HDL不发生降解。结果表明，HDL相关的胆固醇可能通过不同于LDL代谢的途径进行加工。少