Molecular mechanisms of a‐tocopherol transfer protein (a‐TTP)‐dependent a‐tocopherol transfer in hepatocytes

Abstract

α Tocopherol transfer protein (α TTP) is a cytosolic 30 kDa protein that is highly expressed in the liver. α TTP is also known as the causative gene for AVED (ataxia with isolated vitamin E deficiency). Secretion of α tocopherol from hepatocytes by α TTP is essential for the maintenance of plasma α tocopherol concentrations. Although the physiological function of α TTP is well understood, precise mechanisms of α tocopherol transfer by α TTP in hepatocytes remain largely unknown. 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 strongly suggest that α tocopherol transferred to the PIPs enriched inner leaflet of the plasma membrane by α TTP is readily secreted extracellularly by a certain ABC transporter.