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

α-生育酚转移蛋白（α-TTP）是家族性孤立性维生素E缺乏症致病基因的产物。α-TTP从肝细胞分泌α-生育酚对维持血浆α-生育酚浓度是必需的。已知有六种α-TTP点突变会导致AVED。在这些突变中，R59 W特别令人感兴趣。尽管野生型和R59 W α-TTP的α-生育酚结合能力几乎相同，但具有该突变的患者显示出检测不到的血浆维生素E水平和严重的表型。我们发现野生型α-TTP与PIP结合，但R59 W α-TTP不能与PIP结合。此外，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R59 W α-TTP的体外α-生育酚转移活性不随PIP含量的增加而增加。从这些结果中，我们认为α-生育酚通过α-TTP转移到富含PIP的质膜内叶，很容易被细胞分泌到细胞外。 ...更多信息 角鲨烯环氧酶将角鲨烯转化为角鲨烯2，3-氧化物。最近，我们克隆了SPF（上清液蛋白因子）的cDNA，SPF是角鲨烯环氧化的胞浆激活剂。在这项研究中，我们建立了SPF缺陷小鼠，以分析这些小鼠的胆固醇代谢。SPF缺陷小鼠发育正常。然而，我们观察到贝特类，一种抗动脉粥样硬化药物显着降低SPF缺陷小鼠的血浆胆固醇水平。这些数据表明，SPF功能在维持胆固醇稳态在空腹状态下，SPF是一个有前途的目标降胆固醇治疗。25-羟基胆固醇结合到一个特定的胞质受体称为氧固醇结合蛋白（OSBP）。在哺乳动物细胞中，在结合25-羟基胆固醇后，OSBP从细胞质易位到高尔基体。OSBP的一个同源家族，称为ORP家族，已在多种物种中鉴定。在哺乳动物中，该家族包括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。每个蛋白质显示不同的亚细胞定位模式，包括质膜，ER和胞质小泡，表明ORP家族成员的功能不同。少

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