抄録
a-Tocopherol transfer protein (a-TTP) is a cytosolic 30 kDa protein that is highly expressed in the liver. a-TTP is also known as the causative gene for AVED (ataxia with isolated vitamin E deficiency). Affected patients show very low plasma vitamin E levels and consecutively a form of neurodegeneration. Secretion of a-tocopherol from hepatocytes by a-TTP is essential for the maintanance of plasma a-tocopherol concentrations. Although the physiological function of a-TTP is well understood, precise mechanisms of a-tocopherol transfer by a-TTP in hepatocytes remain largely unknown. Brefeldin A, which abolishes a cellular secretion pathway by disrupting the Golgi apparatus, does not affect a-tocopherol secretion from cells. Instead, an ABC transporter inhibitor glyburide reduces a-tocopherol secretion. There are six a-TTP point mutations known to cause AVED. Among these mutations, R59W is of particular interest. Although the a-tocopherol binding capacities of wild-type and R59W a-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 a-TTP binds to PIPs, but R59W a-TTP cannot bind to them. Moreover, the in vitro a-tocopherol transfer activity of the wild-type a-TTP increased with the increasing content of PIPs in the acceptor liposomes, while the transfer activity by R59W a-TTP did not. From these results, we strongly suggest that a-tocopherol transferred to the PIPs enriched inner leaflet of the plasma membrane by a-TTP is readily secreted extracellularly by a certain ABC transporter. [Jpn J Physiol 55 Suppl:S31 (2005)]
