Tocopherol transfer
protein (
TTP) regulates
vitamin E status by facilitating the secretion of
tocopherol from liver to
circulating lipoproteins. Heritable mutations in the
ttpA gene, encoding for
TTP, result in
ataxia with vitamin E deficiency (AVED) syndrome, typified by low
vitamin E levels and a plethora of
neurological disorders. The molecular mechanisms by which
TTP facilitates
tocopherol secretion are presently unknown. We recently showed that
vitamin E is taken up by hepatocytes through an endocytic process and that, shortly following uptake, the
vitamin is found primarily in lysosomes. We showed further that
TTP is localized to late endocytic vesicles and that it facilitates the intracellular trafficking of
tocopherol from lysosomes to the plasma membrane. To gain insight into the molecular mechanisms that underlie
TTP actions, we studied the physiological impact of three naturally occurring heritable mutations in the
ttpA gene (the R59W, R221W, and A120T substitutions). We found that these mutations impair the ability of
TTP to facilitate the secretion of
vitamin E from cells. Furthermore, the degree of impairment corresponded to the severity of the AVED pathology associated with each mutation. In cells that express mutated
TTP proteins,
vitamin E did not traffic to the plasma membrane and remained "trapped" in lysosomes. In addition, we observed that substitution mutations that cause the AVED syndrome impart a marked instability on the
TTP protein. These observations suggest that the physiological role of
TTP is anchored in its ability to direct
vitamin E trafficking from the endocytic compartment to transport vesicles that deliver the
vitamin to the site of secretion at the plasma membrane.