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Physiological and pathological functions of a novel lipid-binding protein family.

新型脂质结合蛋白家族的生理和病理功能。

基本信息

批准号：
13854023
负责人：
ARAI Hiroyuki
金额：
$ 78.79万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (S)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2004
项目状态：
已结题

项目摘要

α-Tocopherol transfer protein(α-TTP) is a product of the causative gene for familial isolated vitamin E deficiency. Secretion of α-tocopherol from hepatocytes by α-TTP is essential for the maintanance of plasma α-tocopherol concentrations. There are six α-TTP point mutations known to cause AVED. Among these mutations, R59W is of particular interest. Although the α-tocopherol binding capacities of wild-type and R59W α-TTP were almost the same, patients with this mutation show undetectable plasma vitamin E levels and a severe phenotype. We have found that wild-type α-TTP binds to PIPs, but R59W α-TTP cannot bind to them. Moreover, the in vitro α-tocopherol transfer activity of the wild-type α-TTP increased with the increasing content of PIPs in the acceptor liposomes, while the transfer activity by R59W α-TTP did not. From these results, we suggest that α-tocopherol transferred to the PIPs enriched inner leaflet of the plasma membrane by α-TTP is readily secreted extracellularly by a cer … More tain ABC transporter.Squalene epoxidase converts squalene to squalene 2,3-oxide. Recently, we cloned the cDNA of SPF(Supernatant Protein Factor), a cytosolic activator of squalene epoxidation. In this study, we established SPF-deficient mice to analyze the cholesterol metabolism in these mice. SPF-deficient mice were normally developed. However, we observed that fibrate, an anti-atherosclerosis drug significantly decreases plasma cholesterol level in SPF-deficient mice. These data indicate that SPF functions in maintaining cholesterol homeostasis in a fasting state, and that SPF is a promising target for cholesterol-lowering therapy.25-hydroxycholesterol binds to a specific cytosolic receptor termed oxysterol-binding protein(OSBP). In mammalian cells, upon binding of 25-hydroxycholesterol, OSBP translocates from cytoplasm to the Golgi apparatus. A family of OSBP homologues, called ORP family, has been identified in a variety of species. In mammal, the family includes 12 genes. Most of their physiological functions and ligands remain to be elucidated. We cloned the all members of the human ORP family and analyzed their subcellular localizations in HeLa cells. Each protein shows different subcellular localization pattern including plasma membrane, ER and cytosolic vesicles, suggesting that the ORP family members are functionally distinct. Less

α-生育酚转移蛋白（α-TTP）是家族性分离性维生素E缺乏症的致病基因产物。肝细胞通过α-TTP分泌α-生育酚对维持血浆α-生育酚浓度至关重要。已知有六种α-TTP点突变可引起AVED。在这些突变中，R59W是特别令人感兴趣的。尽管野生型和R59W α-TTP的α-生育酚结合能力几乎相同，但该突变患者的血浆维生素E水平检测不到，表型严重。我们发现野生型α-TTP能与pip结合，而R59W α-TTP不能与pip结合。野生型α-TTP的体外α-生育酚转移活性随着受体脂质体中pip含量的增加而增加，而R59W α-TTP的体外α-生育酚转移活性则无明显变化。这些结果表明，α-生育酚通过α-TTP转移到富含pip的质膜内小叶，并通过更稳定的ABC转运体在细胞外分泌。角鲨烯环氧化酶将角鲨烯转化为2,3-氧化角鲨烯。最近，我们克隆了角鲨烯环氧化胞浆激活因子SPF（Supernatant Protein Factor）的cDNA。在这项研究中，我们建立了spf缺陷小鼠来分析这些小鼠的胆固醇代谢。spf缺陷小鼠发育正常。然而，我们观察到抗动脉粥样硬化药物贝特可显著降低spf缺陷小鼠的血浆胆固醇水平。这些数据表明，SPF在维持空腹状态下的胆固醇稳态中起作用，SPF是降胆固醇治疗的一个有希望的靶点。25-羟基胆固醇与称为氧甾醇结合蛋白（OSBP）的特定细胞质受体结合。在哺乳动物细胞中，与25-羟基胆固醇结合后，OSBP从细胞质转运到高尔基体。OSBP同源物家族，称为ORP家族，已在多种物种中被发现。在哺乳动物中，这个家族包括12个基因。它们的大部分生理功能和配体仍有待阐明。我们克隆了人类ORP家族的所有成员，并分析了它们在HeLa细胞中的亚细胞定位。每种蛋白都表现出不同的亚细胞定位模式，包括质膜、内质网和细胞质囊泡，这表明ORP家族成员在功能上是不同的。少

项目成果

期刊论文数量（85）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Apolipoprotein-independent efflux of cholesterol and phospholipids by ABCG1

ABCG1 不依赖载脂蛋白的胆固醇和磷脂流出

DOI：
发表时间：
2005
期刊：
J.Biol.Chem. (In press)
影响因子：
0
作者：
Aya Kobayashi;Yasukazu Takanezawa;Takashi Hirata;Yuuji Shimizu;Keiko Misasa;Noriyuki Kioka;Hiroyuki Arai;Kazumitsu Ueda;Michinori Matsuo
通讯作者：
Michinori Matsuo

pH-Dependent fluctuation of a-tocopherol transfer protein (a-TTP) between hepatic cytosol and late endosomes

α-生育酚转移蛋白 (a-TTP) 在肝细胞质和晚期内体之间的 pH 依赖性波动