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

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


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.

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

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Biological Transport, Active / physiology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Endosomes / genetics
  • Endosomes / metabolism*
  • Hepatocytes / cytology
  • Hepatocytes / metabolism*
  • Humans
  • Mutation
  • Receptors, Transferrin / genetics
  • Receptors, Transferrin / metabolism
  • Transferrin / genetics
  • Transferrin / metabolism
  • alpha-Tocopherol / metabolism*
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism


  • Antigens, CD
  • CD71 antigen
  • Carrier Proteins
  • Receptors, Transferrin
  • Transferrin
  • alpha-tocopherol transfer protein
  • RAB8A protein, human
  • rab GTP-Binding Proteins
  • alpha-Tocopherol