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J Biol Chem. 2016 Aug 12;291(33):17028-39. doi: 10.1074/jbc.M116.734210. Epub 2016 Jun 15.

Vitamin E and Phosphoinositides Regulate the Intracellular Localization of the Hepatic α-Tocopherol Transfer Protein.

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From the Departments of Nutrition.
the Department of Chemistry, Brock University, St. Catharines, Ontario L2S 3A1, Canada, and.
the Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853.
Microbiology and Molecular Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
From the Departments of Nutrition, Pharmacology, and


α-Tocopherol (vitamin E) is an essential nutrient for all vertebrates. From the eight naturally occurring members of the vitamin E family, α-tocopherol is the most biologically active species and is selectively retained in tissues. The hepatic α-tocopherol transfer protein (TTP) preferentially selects dietary α-tocopherol and facilitates its transport through the hepatocyte and its secretion to the circulation. In doing so, TTP regulates body-wide levels of α-tocopherol. The mechanisms by which TTP facilitates α-tocopherol trafficking in hepatocytes are poorly understood. We found that the intracellular localization of TTP in hepatocytes is dynamic and responds to the presence of α-tocopherol. In the absence of the vitamin, TTP is localized to perinuclear vesicles that harbor CD71, transferrin, and Rab8, markers of the recycling endosomes. Upon treatment with α-tocopherol, TTP- and α-tocopherol-containing vesicles translocate to the plasma membrane, prior to secretion of the vitamin to the exterior of the cells. The change in TTP localization is specific to α-tocopherol and is time- and dose-dependent. The aberrant intracellular localization patterns of lipid binding-defective TTP mutants highlight the importance of protein-lipid interaction in the transport of α-tocopherol. These findings provide the basis for a proposed mechanistic model that describes TTP-facilitated trafficking of α-tocopherol through hepatocytes.


lipid trafficking; lipid transport; phosphatidylinositol signaling; phosphoinositide; tocopherol; tocopherol transfer protein; vitamin E

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