IUBMB‐Life 2019: Vitamin E—Regulatory Roles

Abstract

Vitamin E has been first recognized as an essential molecule by Evans and Bishop almost 100 years ago, and it therefore is appropriate and timely to dedicate a full thematic issue of IUBMB-Life to its still debated and not yet completely elucidated essential and regulatory functions. In search for a specific transporter and receptor of vitamin E many regulatory effects have been identified and it appears that rather than by acting via one specific target, it affects many. Hence, there is good evidence that vitamin E has regulatory roles in the body—but its molecular mechanisms of action are still subject of investigations. Regulatory effects of vitamin E can be antioxidant/prooxidant by means of its redox-active chemical moieties, or non-antioxidant via interaction of its structural body with receptors, transporters, enzymes and transcription factors, and by modulating membranes and membrane domains such as lipid rafts. To exert regulatory effects vitamin E needs to be efficiently taken up from the diet and distributed in the body and the route taken was for long assumed to be mostly governed by its properties as a hydrophobic molecule. Seminal works done over the last decades revealed that only α-tocopherol (one of the eight natural vitamin E analogues [α-, β-, γ-, δ-tocopherols/tocotrienols] is preferentially enriched in the body by the hepatic α-tocopherol transfer protein [αTTP]), whereas the other seven analogues and excess α-tocopherol are not retained and rapidly metabolized. In addition to αTTP, several more proteins have been discovered that interact with vitamin E and distribute it in the body and in cells. Impaired uptake and transport of α-tocopherol due to genetic mutations in specific genes involved in its transport has been recognized as the reason for primary and secondary vitamin E deficiency syndromes, and in particular of ataxia with vitamin E deficiency (AVED), the main vitamin E deficiency syndrome resulting from αTTP mutations signifying the essential function of α-tocopherol for humans. Interestingly, the vitamin E analogues with lower bioavailability and higher metabolism in vivo have often higher activity at lower concentration in vitro despite their equal value as chemical antioxidants, suggesting that their elimination from the body possibly serves to minimize interference with some cellular functions. To unravel at a molecular level the regulatory roles and biological effects of the eight vitamin E analogues and their metabolites, their interactions with enzymes, receptors, membranes and transport proteins and the function of other natural analogues such as alpha-tocopheryl phosphate and alpha-tocopheryl nicotinate as well of a myriad of synthetic derivatives remains a challenging topic for future investigations. As discussed in this issue (issue 71:4 1-11), many cellular regulatory effects of vitamin E and its metabolites have been recognized modulating apoptosis/cell survival, ferroptosis, cell proliferation, angiogenesis, lipid metabolism, membrane properties and repair, long term potentiation, signal transduction and gene expression. These cellular effects often go beyond a simple antioxidant action and most likely contribute to the beneficial regulatory effects of vitamin E observed in a number of diseases and conditions, ranging from atherosclerosis, inflammation, diabetes, obesity, infection, immune regulation, wound healing, ischemia/reperfusion injury, reproduction, age-related macular degeneration (AMD), neurodegeneration, non-alcoholic steatohepatitis (NASH), cancer/metastasis, senescence and aging.