| It has been appreciated for almost a century that vitamin E is an essential micronutrient. Vitamin E functions as the major lipid soluble antioxidant by protecting lipid bilayers from free radical induced damage. Tocopherol transfer protein (TTP) is the only known regulator of vitamin E status. Our research aims to identify mechanisms that control TTP levels. These results will in turn yield insight into the regulation of vitamin E status. In Immortalized Human Hepatocytes (IHH), TTPA mRNA levels are significantly increased by pharmacological agonists of PPARa, RXR, and CREB, implying lipid metabolism and cAMP levels can regulate TTPA expression. Common single nucleotide polymorphisms present in the TTP promoter region result in variable promoter activity. These data support the notion that by regulating TTP levels, the SNP variants can affect an individual’s vitamin E status. In both IHH and primary cerebellar cells, chemical inducers of oxidative stress increase TTPA mRNA levels, likely as a protective mechanism to facilitate delivery of vitamin E to neighboring cells. Indeed, in radiolabelled secretion assays in mouse primary cerebellar cultures, TTP-expressing astrocytes secrete 50% more tocopherol than neurons. The accumulation of NBD-tocopherol in the lysosomes of cells with attenuated NPC1 and NPC2 protein expression yields insight into vitamin E trafficking in hepatocytes. Importantly, in the NPC1, NPC2 and AD mouse models of human diseases vitamin E plasma levels are within normal range, although tissue levels are altered, suggesting plasma tocopherol levels are not accurate predictors of tissue vitamin E status. Moreover, mis-localization of vitamin E may also contribute to altered vitamin E status. The overall finding that TtpA is regulated in the liver and brain substantiates our hypothesis that TTP functions to maintain specific microenvironments of vitamin E, likely to protect against free radical induced damage, especially in diseased conditions. This notion complements our work in the mouse models of human disease where we report that vitamin E levels are variable throughout the brain. |
