The location and behavior of α‐tocopherol in membranes

Abstract

Vitamin E (a-tocopherol) has long been recognized as the major antioxidant in biological membranes, and yet many structurally related questions persist of how the vitamin functions. For example, the very low levels of a-tocopherol reported for whole cell extracts question how this molecule can successfully protect the comparatively enormous quantities of PUFAcontaining phospholipids found in membranes that are highly susceptible to oxidative attack. The contemporary realization that membranes laterally segregate into regions of distinct lipid composition (domains), we propose, provides the answer. We hypothesize a-tocopherol partitions into domains that are enriched in polyunsaturated phospholipids, amplifying the concentration of the vitamin in the place where it is most needed. These highly disordered domains depleted in cholesterol are analogous, but organizationally antithetical, to the wellstudied lipid rafts. We review here the ideas that led to our hypothesis. Experimental evidence in support of the formation of PUFA-rich domains in model membranes is presented, focusing upon docosahexaenoic acid that is the most unsaturated fatty acid commonly found. Physical methodologies are then described to elucidate the nature of the interaction of a-tocopherol with PUFA and to establish that the vitamin and PUFA-containing phospholipids co-localize in non-raft domains.

δ-Tocopherol Reduces Lipid Accumulation in Niemann-Pick Type C1 and Wolman Cholesterol Storage Disorders

“…These include regulation of enzyme function, cell signaling, cell proliferation, and neuroprotection (43,44). Vitamin E contains a chromanol ring with a hydroxyl group that is responsible for its antioxidant effect and a 13-carbon hydrophobic phytyl side chain that inserts into the plasma membrane (45). ␣-T, the major vitamin E isoform in human plasma, prevents apoptosis induced by 7-ketocholesterol, one of the cholesterol oxidation products in neuronal cells that is markedly increased in NPC1 disease (46).…”

α-Tocopherol incorporation in mitochondria and microsomes upon supranutritional vitamin E supplementation

“…Buttriss and Diplock (1988b) furthermore reported that in different intracellular membranes, there are different proportions of tocopherol not only with respect to total lipids but also to individual polyunsaturated fatty acids. Recently, it has been hypothesized that a-tocopherol partitions into domains of membranes that are enriched in polyunsaturated phospholipids, amplifying the concentration of the vitamin in the place where it is most needed (Atkinson et al 2010).…”

“…The purpose of this review is therefore to briefly summarize experimental data performed with vitamin E treatments provided via the diet in relation to the deposition of a-tocopherol in mitochondria and microsomes. It is beyond the scope of the present study to describe behavior and location of tocopherols and tocotrienols in membranes, as these topics are already covered in the recent excellent reviews by Atkinson et al (2008Atkinson et al ( , 2010.…”

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

“…The rapid and massive uptake of d-T3 and in general of HM forms in cancer cells may influence the lipid structure and key functional domains of the plasmalemma (Atkinson et al 2010).…”

“…These may include a-TTPlike and/or low affinity binding proteins and other proteinlipid and lipid-lipid interactions in cell membranes and in the cytosol (Atkinson et al 2008), as well as intracellular receptors such as ERb (Comitato et al 2009), and orphan receptors such as SXR (Zhou et al 2004) and PXR (Brigelius-Flohe 2005). As a consequence of a specific structure-function and in analogy with the behavior of a-TOH, T3 may co-localize and interact with PUFA and cholesterol molecules in the membrane to influence the composition and signaling function of membrane microdomains such as the ''membrane rafts'' (Atkinson et al 2008(Atkinson et al , 2010, which are increasing their recognition as regions of the plasmalemma that may control cell signaling and redox responses through key elements such as the enzyme NADPH-oxidase and PKC (Galli 2007a, b). Specificity of T3 signaling includes the control of this latter protein kinase (Eitsuka et al 2006) as well as of other kinases such as PI3K/Akt (Shah and Sylvester 2004;Shibata et al 2008;Uto-Kondo et al 2009) and ERK-MAPK (Sun et al 2008) and cyclin-dependent kinases (Elangovan et al 2008).…”