Vitamin E: Mechanism of transport and regulation in the CNS

Abstract

Although vitamin E has been recognized as a critical micronutrient to neuronal health for more than half a century, vitamin E transport and regulation in the brain remain a mystery. Currently, the majority of what is known about vitamin E transport has been delineated in the liver. However, clues from the pathogenesis of neurological‐related vitamin E deficient diseases point to compromised neuronal integrity and function, underlining the critical need to understand vitamin E regulation in the CNS. Additionally, most of the same molecular players involved in vitamin E transport in the liver are also found in CNS, including sterol SRB1, TTP, and ABCA/ABCG, suggesting similar intracellular pathways between these organ systems. Finally, based on chemical similarities, intracellular CNS shuttling of vitamin E likely resembles cholesterol's use of ApoE particles. Utilizing this information, this review will address what is currently known about trafficking vitamin E across the blood brain barrier in order to ensure an adequate supply of the essential nutrient to the brain. Although debatable, the health of the brain in relation to vitamin E levels has been demonstrated, most notably in oxidative stress‐related conditions such as ataxias, Alzheimer's disease, and Parkinson's disease. Future vitamin E research is vital in understanding how the regulation of the vitamin can aid in the prevention, treatment, and curing of neurological diseases. © 2018 IUBMB Life, 71(4):424–429, 2019

Neuroprotective Effect of Antioxidants in the Brain

“…Vitamin E is a major group of lipid-soluble antioxidants called tocopherols and tocotrienols, of which the most biologically active isoform is α-tocopherol [ 154 ]. It is a major chain-breaking antioxidant and exists in a low molar ratio compared to unsaturated phospholipids.…”

“…It is a major chain-breaking antioxidant and exists in a low molar ratio compared to unsaturated phospholipids. The most important function of vitamin E is its antioxidant activity, which protects the integrity of cellular membranes from polyunsaturated fatty acid-generated oxygen free radicals and to act as a direct scavenger of superoxide and hydroxyl radicals [ 154 , 155 ]. Based on studies of brain capillary endothelial cells, the mechanism of entry of α-tocopherol into the CNS correlated to α-tocopherol and scavenger receptor class B type 1 (SRB1) levels.…”

“…Once α-tocopherol passes through the BBB, it may be directly delivered to specialized astrocytes. Astrocyte-synthesized apolipoprotein E (ApoE) moves through the cerebral spinal fluid transporting α-tocopherol between various cell types in the CNS cell [ 154 , 159 ]. ApoE lipoprotein particles in astrocytes are secreted through membrane proteins and interact with low-density lipoprotein receptor-related protein (LRP) on the neurons [ 160 ].…”

“…ATRA regulates gene transcription through retinoic acid receptors (RAR) and/or retinoid X receptors (RXRs) which are bound to retinoic acid response elements (RARE) in the nucleus. These representative schematics are modified from [ 130 , 154 , 161 ]. Abbreviations: VC, vitamin C; VE, vitamin E; VA, vitamin A; ASC, ascorbate; ASF, ascorbate free radical; DHA, dehydroascorbic acid; GLUT1, glucose transports; SVTC-2, sodium-dependent transporters; LRP, lipoprotein receptor-related protein; GSH, glutathione; ApoE, apolipoprotein E; HDL, density lipoprotein; CMRE, chylomicron remnant; CRABP, cellular retinoic acid-binding protein; LRAT, lethicin: retinol acyltransferase; RBP, retinol binding protein; RAL, retinaldehyde; RDH/ADH, retinol dehydrogenase; RALDH, retinaldehyde dehydrogenase; RXR, retinoid X receptors; RAR, retinoic acid receptors; ATRA, all-trans-retinoic acid; BBB, blood–brain barrier.…”

IUBMB‐Life 2019: Vitamin E—Regulatory Roles

“…As discussed in this issue (issue 71:4 ), 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.…”