Vitamin E and Phosphoinositides Regulate the Intracellular Localization of the Hepatic α-Tocopherol Transfer Protein.
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.
From the Departments of Nutrition.
Stacey
S
Chung
the Department of Chemistry, Brock University, St. Catharines, Ontario L2S 3A1, Canada, and.
Mikel
M
Ghelfi
the Department of Chemistry, Brock University, St. Catharines, Ontario L2S 3A1, Canada, and.
Jeffrey
J
Atkinson
the Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853.
Robert
R
Parker
the Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853.
Jinghui
J
Qian
Microbiology and Molecular Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
Cathleen
C
Carlin
From the Departments of Nutrition, Pharmacology, and dxm178@case.edu.
Danny
D
Manor
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001693:Biological Transport, Active / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D014168:Transferrin / Q000235:genetics / Q000378:metabolism; D024502:alpha-Tocopherol / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; C068126:CD71 antigen; D002352:Carrier Proteins; D011990:Receptors, Transferrin; D014168:Transferrin; C017763:alpha-tocopherol transfer protein; C082377:RAB8A protein, human; D020691:rab GTP-Binding Proteins; D024502:alpha-Tocopherol
lipid trafficking; lipid transport; phosphatidylinositol signaling; phosphoinositide; tocopherol; tocopherol transfer protein; vitamin E