Non‐antioxidant molecular functions of α‐tocopherol (vitamin E)

Azzi, Angelo; Ricciarelli, Roberta; Zingg, Jean Marc

doi:10.1016/s0014-5793(02)02706-0

Cited by 284 publications

(165 citation statements)

References 50 publications

(51 reference statements)

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“…For example, vitamin E inhibits protein kinase C by a nonantioxidant mechanism (25). Vitamin E also accelerates diacylglycerol kinase activity, thereby decreasing levels of diacylglycerol, which is an allosteric activator of protein kinase C (26).…”

Section: Statisticsmentioning

confidence: 99%

Effect of High-Dose Vitamin E on Insulin Resistance and Associated Parameters in Overweight Subjects

et al. 2004

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OBJECTIVE -Markers of oxidative stress and plasma alanine transferase (ALT) levels are increased and circulating antioxidant concentrations are reduced in individuals with insulin resistance. Vitamin E improves glycemic control in people with diabetes. We tested the hypothesis that vitamin E would decrease markers of oxidative stress and plasma ALT levels and improve insulin sensitivity in overweight individuals. RESEARCH DESIGN AND METHODS -Eighty overweight individuals (BMI Ͼ27 kg/m2 ) were randomly allocated to receive either 800 IU vitamin E per day or a matching placebo for 3 months. The dose of vitamin E was increased to 1,200 IU per day for a further 3 months.RESULTS -Plasma peroxides decreased by 27% at 3 months and by 29% at 6 months in the group that received vitamin E and were positively correlated with plasma vitamin E concentrations at the 6-month time point. At 3 months, fasting plasma glucose and insulin concentrations were significantly reduced and homeostasis model assessment increased. These changes were not apparent at 6 months. Plasma ALT concentrations declined significantly throughout the study period.CONCLUSIONS -In conclusion, these findings indicate that vitamin E improves oxidative stress and hepatocellular function. Although insulin resistance also improves, this effect appears transient. Diabetes Care 27:2166 -2171, 2004T he prevalence of diabetes is increasing dramatically in the western world (1). This increase parallels that of obesity, with insulin resistance explaining the link between these two entities (2). Although the precise mechanism responsible for insulin resistance remains unclear, it would appear that a number of adipocyte-derived factors impair insulin activity and that the secretion of these factors is altered in the obese individual (3). Diabetes results when, in addition to insulin resistance, ␤-cell dysfunction occurs, leading to relative insulin deficiency. Interventions shown to be effective at preventing the progression to diabetes include lifestyle modification (4,5) and certain pharmacologic agents (4,6).One of the adipocyte-derived factors implicated in the pathogenesis of insulin resistance is the free fatty acid (FFA) (7). Although the rate of release of FFAs from individual adipocytes may not be raised in obesity, the increased amount of adipose tissue overall leads to an increase in the flux of FFAs to the liver and skeletal muscle, the two tissues most intimately involved in glucose handling (8). Once FFAs enter target tissues, they are either stored as triglycerides or are utilized as a substrate for oxidation by the cell's mitochondria. As a result of the normal process of oxidation, reactive oxygen species (ROS) are produced (9). These ROS are potentially harmful to cellular functions. To prevent these harmful effects, the cell has developed a complex antioxidant system to dispose of ROS. However, antioxidant concentrations are reduced in obese individuals, and the resulting imbalance between the production of ROS and antioxidant defenses results in o...

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Section: Statisticsmentioning

confidence: 99%

Effect of High-Dose Vitamin E on Insulin Resistance and Associated Parameters in Overweight Subjects

et al. 2004

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“…Section 1734 solely to indicate this fact. 4 The abbreviations used are: ROS, reactive oxygen species; DEPMPO, 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide; DHE, dihydroethidium; ETC, electron transport chain; HPLC, high performance liquid chromatography; RCR, respiratory control ratio; TTP, tocopherol transfer protein; VED, vitamin E-deficient; F2-IsoP, F2-isoprostane. …”

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confidence: 99%

“…The mechanism by which these "nonantioxidant" actions factor into the observed biological effects of ␣-tocopherol is not yet known. A systematic study of the relationship between levels of ␣-tocopherol and ROS 4 production is one approach to begin to differentiate the documented ability of ␣-tocopherol to act as a lipid peroxidation inhibitor and antioxidant versus its other potential activities in vivo.…”

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confidence: 99%

Prolonged α-Tocopherol Deficiency Decreases Oxidative Stress and Unmasks α-Tocopherol-dependent Regulation of Mitochondrial Function in the Brain

Cuddihy

Ali

Musiek

et al. 2008

Journal of Biological Chemistry

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Vitamin E is the major lipid-soluble chain-breaking antioxidant in mammals and plays an important role in normal development and physiology. Deficiency (whether dietary or genetic) results in primarily nervous system pathology, including cerebellar neurodegeneration and progressive ataxia (abnormal gait). However, despite the widely acknowledged antioxidant properties of vitamin E, only a few studies have directly correlated levels of reactive oxygen species with vitamin E availability in animal models. We explored the relationship between vitamin E and reactive oxygen species in two mouse models of vitamin E deficiency: dietary deficiency and a genetic model (tocopherol transfer protein, Ttp ؊/؊ mice). Both groups of mice developed nearly complete depletion of ␣-tocopherol (the major tocopherol in vitamin E) in most organs, but not in the brain, which was relatively resistant to loss of ␣-tocopherol. F4-neuroprostanes, an index of lipid peroxidation, were unexpectedly lower in brains of deficient mice compared with controls. In vivo oxidation of dihydroethidium by superoxide radical was also significantly lower in brains of deficient animals. Superoxide production by brain mitochondria isolated from vitamin E-deficient and Ttp ؊/؊ mice, measured by electron paramagnetic resonance spectroscopy, demonstrated a biphasic dependence on exogenously added ␣-tocopherol. At low concentrations, ␣-tocopherol enhanced superoxide flux from mitochondria, a response that was reversed at higher concentrations. Here we propose a mechanism, supported by molecular modeling, to explain decreased superoxide production during ␣-tocopherol deficiency and speculate that this could be a beneficial response under conditions of ␣-tocopherol deficiency.␣-Tocopherol was first discovered as a micronutrient indispensable for reproduction in female rats (1). The view that ␣-tocopherol functions solely as a chain-breaking antioxidant has prevailed, reflecting a large body of accumulated experimental evidence showing that ␣-tocopherol can reduce lipid peroxidation in many models and the observation that ␣-tocopherol inhibits lipid peroxidation by scavenging peroxyl radicals faster (10 6 M Ϫ1 s Ϫ1 ) than they can react with other lipids (ϳ10 2 M Ϫ1 s Ϫ1 ) or proteins (2). Recently, however, a broad array of "nonantioxidant" cellular functions for ␣-tocopherol have emerged (reviewed in Refs. 3-8, but see Ref. 9 for the opposing view that supports a pure antioxidative function for ␣-tocopherol). The mechanism by which these "nonantioxidant" actions factor into the observed biological effects of ␣-tocopherol is not yet known. A systematic study of the relationship between levels of ␣-tocopherol and ROS 4 production is one approach to begin to differentiate the documented ability of ␣-tocopherol to act as a lipid peroxidation inhibitor and antioxidant versus its other potential activities in vivo.In the current study, we used two mouse models of vitamin E deficiency: 1) dietary deficiency (VED) in C57BL6 mice and 2) a genetic model, ␣-tocopherol tra...

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“…Sattler et al (2003) postulated that additional biological activities of tocopherols, which are not related to their antioxidant function, might be involved in the different responses of Arabidopsis and maize to tocopherol deficiency. There is accumulating evidence from studies in mammalian systems that specific tocopherols are able to modulate signal transduction pathways or act as signal molecules themselves (for review, see Azzi et al, 2002;Rimbach et al, 2002). Although direct evidence for analogous nonantioxidant roles of tocopherols in plants is lacking, it was speculated that tocopherol deficiency in sxd1 interfered with signal transduction events that are required specifically for the formation of BS-VP PD .…”

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RNAi-Mediated Tocopherol Deficiency Impairs Photoassimilate Export in Transgenic Potato Plants

et al. 2004

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Tocopherols (vitamin E) are lipophilic antioxidants presumed to play a key role in protecting chloroplast membranes and the photosynthetic apparatus from photooxidative damage. Additional nonantioxidant functions of tocopherols have been proposed after the recent finding that the Suc export defective1 maize (Zea mays) mutant (sxd1) carries a defect in tocopherol cyclase (TC) and thus is devoid of tocopherols. However, the corresponding vitamin E deficient1 Arabidopsis mutant (vte1) lacks a phenotype analogous to sxd1, suggesting differences in tocopherol function between C4 and C3 plants. Therefore, in this study, the potato (Solanum tuberosum) ortholog of SXD1 was isolated and functionally characterized. StSXD1 encoded a protein with high TC activity in vitro, and chloroplastic localization was demonstrated by transient expression of green fluorescent protein-tagged fusion constructs. RNAi-mediated silencing of StSXD1 in transgenic potato plants resulted in the disruption of TC activity and severe tocopherol deficiency similar to the orthologous sxd1 and vte1 mutants. The nearly complete absence of tocopherols caused a characteristic photoassimilate export-defective phenotype comparable to sxd1, which appeared to be a consequence of vascular-specific callose deposition observed in source leaves. CO 2 assimilation rates and photosynthetic gene expression were decreased in source leaves in close correlation with excess sugar accumulation, suggesting a carbohydrate-mediated feedback inhibition rather than a direct impact of tocopherol deficiency on photosynthetic capacity. This conclusion is further supported by an increased photosynthetic capacity of young leaves regardless of decreased tocopherol levels. Our data provide evidence that tocopherol deficiency leads to impaired photoassimilate export from source leaves in both monocot and dicot plant species and suggest significant differences among C3 plants in response to tocopherol reduction.

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Non‐antioxidant molecular functions of α‐tocopherol (vitamin E)

Cited by 284 publications

References 50 publications

Effect of High-Dose Vitamin E on Insulin Resistance and Associated Parameters in Overweight Subjects

Effect of High-Dose Vitamin E on Insulin Resistance and Associated Parameters in Overweight Subjects

Prolonged α-Tocopherol Deficiency Decreases Oxidative Stress and Unmasks α-Tocopherol-dependent Regulation of Mitochondrial Function in the Brain

RNAi-Mediated Tocopherol Deficiency Impairs Photoassimilate Export in Transgenic Potato Plants

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