On the existence of cellular tocopheryl phosphate, its synthesis, degradation and cellular roles: A hypothesis

The finding that alpha-tocopheryl phosphate is present in cells in small amounts, that it can be synthesized and hydrolyzed supports the hypothesis that alpha-tocopheryl phosphate might be a signaling molecule. The possible pathways needed for the synthesis, hydrolysis and signaling are considered in this hypothesis as well the possible extension of this reaction to additional molecules such as tocopherols and tocotrienols. A possible mechanism of action of other tocopherol esters (succinate and maleate) is also hypothesized

Modulation of Phosphorylation of Tocopherol and Phosphatidylinositol by hTAP1/SEC14L2-Mediated Lipid Exchange

The vitamin E derivative, alpha-tocopheryl phosphate (αTP), is detectable in cultured cells, plasma and tissues in small amounts, suggesting the existence of enzyme(s) with α-tocopherol (αT) kinase activity. Here, we characterize the production of αTP from αT and [γ-32P]-ATP in primary human coronary artery smooth muscle cells (HCA-SMC) using separation by thin layer chromatography (TLC) and subsequent analysis by Ultra Performance Liquid Chromatography (UPLC). In addition to αT, although to a lower amount, also γT is phosphorylated. In THP-1 monocytes, γTP inhibits cell proliferation and reduces CD36 scavenger receptor expression more potently than αTP. Both αTP and γTP activate the promoter of the human vascular endothelial growth factor (VEGF) gene with similar potency, whereas αT and γT had no significant effect. The recombinant human tocopherol associated protein 1 (hTAP1, hSEC14L2) binds both αT and αTP and stimulates phosphorylation of αT possibly by facilitating its transport and presentation to a putative αT kinase. Recombinant hTAP1 reduces the in vitro activity of the phosphatidylinositol-3-kinase gamma (PI3Kγ) indicating the formation of a stalled/inactive hTAP1/PI3Kγ heterodimer. The addition of αT, βT, γT, δT or αTP differentially stimulates PI3Kγ, suggesting facilitated egress of sequestered PI from hTAP1 to the enzyme. It is suggested that the continuous competitive exchange of different lipophilic ligands in hTAPs with cell enzymes and membranes may be a way to make these lipophiles more accessible as substrates for enzymes and as components of specific membrane domains

Interaction Between Vitamin E and Polyunsaturated Fatty Acids

Polyunsaturated fatty acids (PUFA) are nutritionally essential since they cannot be synthesized de novo from two-carbon fragments. As a result of their unsaturated double bonds, PUFA are susceptible to chemical reactions with reactive oxygen and nitrogen species (ROS and RNS, respectively). PUFA incorporated into phospholipids and present in biological membranes not only influence membrane fluidity, curvature, and the properties of membrane microdomains, but increase also the risk for chain reactions of lipid peroxidation leading to membrane destabilization and cellular dysfunction. Vitamin E, the main lipid-soluble antioxidant, stabilizes membranes by itself and protects PUFA by scavenging lipid peroxyl radicals. Thus, vitamin E and PUFA form an interdependent chemical pair in which vitamin E protects PUFA, whereas excess PUFA “consume” vitamin E, a high PUFA/vitamin E ratio being generally assumed as disadvantageous. In cells, both PUFA and vitamin E have their own redox-independent regulatory functions, mostly after being metabolized to active lipid mediators able to bind to specific enzymes and receptors involved in modulating specific signal transduction and gene expression pathways. Thus, the efficiency of uptake, transport, and metabolism of vitamin E and PUFA, their interaction, and their consequent relative levels in cells and tissues are important determinants for both physiological and pathophysiological cellular functions and therefore influence the risk for a number of diseases