Vitamin E and neurologic function in man

Despite the well-known detrimental effect of vitamin E deficiency on the nervous system of many experimental animal models for decades, only over the past decade has vitamin E become recognized as essential for the maintenance of the structure and function of the human nervous system. This discovery of the neurologic role of vitamin E in man is due primarily to the identification of a degenerative neurologic syndrome in children and adults with chronic vitamin E deficiency caused by gastrointestinal diseases impairing fat and vitamin E absorption. A compelling body of clinical, neuropathologic, and therapeutic response evidence conclusively demonstrates that vitamin E deficiency is responsible for the neurologic disorder seen in such patients. In addition, an inborn error in vitamin E metabolism, the Isolated Vitamin E Deficiency Syndrome, causes vitamin E deficiency and similar neurologic degeneration in the absence of fat malabsorption. Guidelines for the evaluation and treatment of vitamin E deficiency in relevant clinical circumstances are provided. The possible role of vitamin E in treating other neurologic diseases is discussed.     

Wolcott-Rallison syndrome

Familial hypocholesterolemia, namely abetalipoproteinemia, hypobetalipoproteinemia and chylomicron retention disease (CRD), are rare genetic diseases that cause malnutrition, failure to thrive, growth failure and vitamin E deficiency, as well as other complications. Recently, the gene implicated in CRD was identified. The diagnosis is often delayed because symptoms are nonspecific. Treatment and follow-up remain poorly defined. The aim of this paper is to provide guidelines for the diagnosis, treatment and follow-up of children with CRD based on a literature overview and two pediatric centers 'experience. The diagnosis is based on a history of chronic diarrhea with fat malabsorption and abnormal lipid profile. Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present. Creatine kinase (CK) is usually elevated and hepatic steatosis is common. Genotyping identifies the Sar1b gene mutation. Treatment should be aimed at preventing potential complications. Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet. Failure to thrive is one of the most common initial clinical findings. Neurological and ophthalmologic complications in CRD are less severe than in other types of familial hypocholesterolemia. However, the vitamin E deficiency status plays a pivotal role in preventing neurological complications. Essential fatty acid (EFA) deficiency is especially severe early in life. Recently, increased CK levels and cardiomyopathy have been described in addition to muscular manifestations. Poor mineralization and delayed bone maturation do occur. A moderate degree of macrovesicular steatosis is common, but no cases of steatohepatitis cirrhosis. Besides a low-long chain fat diet made up uniquely of polyunsaturated fatty acids, treatment includes fat-soluble vitamin supplements and large amounts of vitamin E. Despite fat malabsorption and the absence of postprandial chylomicrons, the oral route can prevent neurological complications even though serum levels of vitamin E remain chronically low. Dietary counseling is needed not only to monitor fat intake and improve symptoms, but also to maintain sufficient caloric and EFA intake. Despite a better understanding of the pathogenesis of CRD, the diagnosis and management of the disease remain a challenge for clinicians. The clinical guidelines proposed will helpfully lead to an earlier diagnosis and the prevention of complications.     

Vitamin E and neurodegenerative diseases

Vitamin E is essential for neurological function. This fact, together with a growing body of evidence indicating that neurodegenerative processes are associated with oxidative stress, lead to the convincing idea that several neurological disorders may be prevented and/or cured by the antioxidant properties of vitamin E.

In this review, some aspects related to the role of vitamin E against Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and ataxia with vitamin E deficiency will be presented.     

Thiocyanate Metabolism in Human Vitamin B12 Deficiency

Patients with subacute combined degeneration who smoked had significantly lowered plasma thiocyanate levels than control smokers, but plasma thiocyanate levels in non-smoking patients with neurological disease due to vitamin B₁₂ deficiency were not significantly different from control values. The results provide no support for the hypothesis that chronic cyanide intoxication is responsible for the occurrence of neurological disease in a minority of patients with vitamin B₁₂ deficiency, although they do not conclusively exclude this possibility. The association between smoking and subacute combined degeneration of the cord has been confirmed in this study but it remains unexplained.     

Vitamin E deficiency impairs the somatostatinergic receptor–effector system and leads to phosphotyrosine phosphatase overactivation and cell death in the rat hippocampus

Vitamin E plays an essential role in maintaining the structure and function of the nervous system, and its deficiency, commonly associated with fat malabsorption diseases, may reduce neuronal survival. We previously demonstrated that the somatostatinergic system, implicated in neuronal survival control, can be modulated by α-tocopherol in the rat dentate gyrus, increasing cyclic adenosine monophosphate response element binding protein phosphorylation. To gain a better understanding of the molecular actions of tocopherols and examine the link among vitamin E, somatostatin and neuronal survival, we have investigated the effects of a deficiency and subsequent administration of tocopherol on the somatostatin signaling pathway and neuronal survival in the rat hippocampus. No changes in somatostatin expression were detected in vitamin-E-deficient rats. These rats, however, showed a significant increase in the somatostatin receptor density and dissociation constant, which correlated with a significant increase in the protein levels of somatostatin receptors. Nevertheless, vitamin E deficiency impaired the ability of the somatostatin receptors to couple to the effectors adenylyl cyclase and phosphotyrosine phosphatase by diminishing Gi protein functionality. Furthermore, vitamin E deficiency significantly increased phosphotyrosine phosphatase activity and PTPη expression, as well as PKCδ activation, and decreased extracellular-signal-regulated kinase phosphorylation. All these changes were accompanied by an increase in neuronal cell death. Subsequent α-tocopherol administration partially or completely reversed all these values to control levels. Altogether, our results prove the importance of vitamin E homeostasis in the somatostatin receptor–effector system and suggest a possible mechanism by which this vitamin may regulate the neuronal cell survival in the adult hippocampus.     

Clinical uses and abuses of vitamin E in children.

The major benefits arising from elevated dosages of vitamin E have been the relief of symptoms of vitamin E deficiency in humans with abetalipoproteinemia and chronic cholestasis. In addition, supplements of vitamin E prevent the isolated vitamin E deficiency that has recently been associated with spinocerebellar symptoms. In keeping with the view that newborn infants, and especially premature infants, suffer from vitamin E deficiency, elevated dosages of vitamin E have been administered to prevent the anemia of premature infants, retrolental fibroplasia, bronchopulmonary dysplasia, and intraventricular hemorrhage. However, the results have been conflicting. Furthermore, some infants treated with vitamin E die unexpectedly. The life-threatening hazard of such treatments has been attributed mainly to polysorbates that are used as detergents in preparations of vitamin E for intravenous use rather than to vitamin E itself. The possibility that vitamin E, in its action as an antioxidant, inhibits the generation of superoxide anion in leukocytes is examined in this paper.     

Vitamin E: underestimated as an antioxidant

Some 80 years after its discovery, vitamin E has experienced a renaissance which is as surprising as it is trivial. Although vitamin E is essential for reproduction, in rats at least, and deficiency causes neurological disorders in humans, the main interest in the last decades has concentrated on its antioxidant functions. This focus has highly underestimated the biological importance of vitamin E, which by far exceeds the need for acting as a radical scavenger. Only recently has it become clear that vitamin E can regulate cellular signaling and gene expression. Out of the eight different tocols included in the term vitamin E, alpha-tocopherol often exerts specific functions, which is also reflected in its selective recognition by proteins such as the alpha-tocopherol transfer protein and alpha-tocopherol-associated proteins. Vitamin E forms other than alpha-tocopherol are very actively metabolised, which explains their low biopotency. In vivo, metabolism may also attenuate the novel functions of gamma-tocopherol and tocotrienols observed in vitro. On the other hand, metabolites derived from individual forms of vitamin E have been shown to exert effects by themselves. This article focuses on the metabolism and novel functions of vitamin E with special emphasis on differential biological activities of individual vitamin E forms.     

植物维生素E生物强化研究进展

维生素E是一种只能在光合组织中合成的脂溶性小分子有机化合物,是人体和动物营养不可缺少的重要维生素。由于植物中维生素E含量较低,人类大多处于慢性缺乏维生素E--“隐性饥饿”的状态,而动物饲料中则需要添加外源合成的维生素E以满足其营养需求。因此,提高植物中维生素E的含量是改善维生素E缺乏的重要途径之一。从维生素E的合成途径入手,详细地综述了维生素E合成关键酶基因的表达变化以及前体物质的含量变化对维生素E合成的影响,发现三烯生育酚和α-生育酚的生物强化效果较好,而生育酚总量提高受限;进而从遗传的角度探讨了维生素E合成受限的原因以及遗传上可能影响维生素E合成的其他代谢途径;最后结合可能影响维生素E合成的调控因子以及其前体物质的转运等方面为今后维生素E的生物强化提出了新的思路。     

Brown fat thermogenesis and exercise: two examples of physiological oxidative stress?

Both brown fat tissue (BAT) and skeletal muscle experience large increases of oxygen consumption and oxygen radical generation during activation. This, together with the relatively low activities of antioxidant enzymes in these two tissues and the high lipid content and free fatty acid liberation of BAT, can produce a physiological oxidative stress. Increases of in vivo or in vitro (BAT) lipid peroxidation have been described in these tissues after activation. They react to this oxidative stress in an adaptive way after chronic stimulation. Cold acclimation increases antioxidant enzymes, ascorbate, and especially reduced glutathione (GSH) in BAT. There is controversy about the variations of antioxidants in skeletal muscle after acute exercise. Nevertheless, exercise training seems to increase muscle antioxidant enzymes and GSH. Many reports show that vitamin E levels decrease in the muscle and increase in plasma during exercise. Studies of vitamin E deficiency and supplementation strongly suggest that this vitamin is of protective value during exercise.     

Vitamin E revisited: do new data validate benefits for chronic disease prevention?

PURPOSE OF REVIEW: Vitamin E benefits in human health and chronic disease prevention are evaluated with respect to established alpha-tocopherol functions during vitamin E deficiency, adequacy, and excess. RECENT FINDINGS: Baseline vitamin E status of the 29 092 Finnish men participating in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study showed that the men in the highest compared with the lowest quintile of serum alpha-tocopherol had significantly lower incidences of total and cause-specific mortality. New findings from the Women's Health Study support a role for vitamin E supplements in decreasing the risk for sudden death from cardiovascular disease and from thromboembolism. We speculate that a potential mechanism may involve vitamin E interference in vitamin K activation. SUMMARY: alpha-Tocopherol acts as a peroxyl and alkoxyl radical scavenger in lipid environments, and thus it prevents lipid peroxidation in lipoproteins and membranes, especially nervous tissues. Decreased chronic disease incidence is associated with lifelong generous dietary vitamin E intakes, but more than 90% of Americans do not consume the recommended dietary amounts (15 mg/day). Vitamin E supplements can have beneficial effects on health beyond those from dietary amounts, perhaps because pharmacologic levels also upregulate hepatic xenobiotic pathways.     

Etiologic factors and pathologic alterations in selenium-vitamin E deficiency and excess in animals and humans

The etiology of selenium-vitamin E (Se-E) deficiency diseases may be complex. Many of the syndromes involve combined deficiency of selenium and vitamin E. Selenium moves into the animal and human food chain from soil and plants, which may contain inadequate amounts of the nutrient in many areas of the world. Vitamin E may be in low concentration in many animal feeds unless supplements are added. Some syndromes, such as steatitis in cats, result from an increased requirement of vitamin E in diets that contain large amounts of polyunsaturated fatty acids, and these diseases will only respond to vitamin E administration. Deficiency syndromes in animals owing to pure Se deficiency are infrequent and have been produced mainly by laboratory studies utilizing extreme deficiency conditions. Other factors that may affect the occurrence of these deficiency diseases are concurrent dietary deficiency of S-containing amino acids, bioavailability of different forms of dietary Se, intake of compounds that antagonize Se (e.g., silver salts), and exposure to various prooxidant substances (e.g., iron compounds, oxygen, ozone, and various drugs). A wide variety of pathologic alterations occur in animals and humans with Se-E deficiency. Myocardial lesions are seen most frequently in calves, lambs, pigs, turkey poults, and ducklings. In humans, Keshan disease, an endemic cardiomyopathy in China, is attributed to Se deficiency. Necrosis of skeletal muscle is the most frequent lesion observed in animal species. Necrosis of smooth muscle of the gizzard and intestine may be a prominent lesion in turkey poults, ducklings, and quail. Other Se-E deficiency lesions include hepatic necrosis, gastric ulceration, intestinal and uterine lipofuscinosis, pancreatic damage, steatitis, exudative diathesis, encephalomalacia, and testicular necrosis. Selenium toxicosis is well characterized in animals and humans by neurological, hoof, and hair alterations.     

Pancreas disease in Atlantic salmon (Salmo salar) and vitamin E supplementation

A study was instigated to investigate the histopathological and clinical pathological lesions associated with a naturally occurring pancreas disease (PD) outbreak in farmed Atlantic salmon. An attempt was made to reduce the severity of PD and associated lesions by altering the antioxidative and peroxidative substrates in the diets. The results do not support the hypothesis that PD leads to a vitamin E deficiency which induces a myopathy. PD was not associated with a reduction in tissue vitamin E concentrations. Despite high tissue vitamin E concentrations, pancreatic lesions and cardiac and skeletal myopathy occurred amiost simultaneously. Severe myopathy appeared to be associated with high mortality. Dietary vitamin E concentrations > 500 mg/kg did not increase plasma and muscle vitamin E concentrations, which appear to be saturated. Liver concentrations were also high. However, differing concentrations of dietary vitamin E and fat were associated with differing mortality rates.     

Vitamin E: underestimated as an antioxidant

Abstract

Some 80 years after its discovery, vitamin E has experienced a renaissance which is as surprising as it is trivial. Although vitamin E is essential for reproduction, in rats at least, and deficiency causes neurological disorders in humans, the main interest in the last decades has concentrated on its antioxidant functions. This focus has highly underestimated the biological importance of vitamin E, which by far exceeds the need for acting as a radical scavenger. Only recently has it become clear that vitamin E can regulate cellular signaling and gene expression. Out of the eight different tocols included in the term vitamin E, α-tocopherol often exerts specific functions, which is also reflected in its selective recognition by proteins such as the α-tocopherol transfer protein and α-tocopherol-associated proteins. Vitamin E forms other than α-tocopherol are very actively metabolised, which explains their low biopotency. In vivo, metabolism may also attenuate the novel functions of γ-tocopherol and tocotrienols observed in vitro. On the other hand, metabolites derived from individual forms of vitamin E have been shown to exert effects by themselves. This article focuses on the metabolism and novel functions of vitamin E with special emphasis on differential biological activities of individual vitamin E forms.     

Biochemical consequences of heritable mutations in the alpha-tocopherol transfer protein

Tocopherol transfer protein (TTP) regulates vitamin E status by facilitating the secretion of tocopherol from liver to circulating lipoproteins. Heritable mutations in the ttpA gene, encoding for TTP, result in ataxia with vitamin E deficiency (AVED) syndrome, typified by low vitamin E levels and a plethora of neurological disorders. The molecular mechanisms by which TTP facilitates tocopherol secretion are presently unknown. We recently showed that vitamin E is taken up by hepatocytes through an endocytic process and that, shortly following uptake, the vitamin is found primarily in lysosomes. We showed further that TTP is localized to late endocytic vesicles and that it facilitates the intracellular trafficking of tocopherol from lysosomes to the plasma membrane. To gain insight into the molecular mechanisms that underlie TTP actions, we studied the physiological impact of three naturally occurring heritable mutations in the ttpA gene (the R59W, R221W, and A120T substitutions). We found that these mutations impair the ability of TTP to facilitate the secretion of vitamin E from cells. Furthermore, the degree of impairment corresponded to the severity of the AVED pathology associated with each mutation. In cells that express mutated TTP proteins, vitamin E did not traffic to the plasma membrane and remained "trapped" in lysosomes. In addition, we observed that substitution mutations that cause the AVED syndrome impart a marked instability on the TTP protein. These observations suggest that the physiological role of TTP is anchored in its ability to direct vitamin E trafficking from the endocytic compartment to transport vesicles that deliver the vitamin to the site of secretion at the plasma membrane.     

Iron uncouples oxidative phosphorylation in brain mitochondria isolated from vitamin E-deficient rats

Few, if any, studies have examined the effect of vitamin E deficiency on brain mitochondrial oxidative phosphorylation. The latter was studied using brain mitochondria isolated from control and vitamin E-deficient rats (13 months of deficiency) after exposure to iron, an inducer of oxidative stress. Mitochondria were treated with iron (2 to 50 microM) added as ferrous ammonium sulfate. Rates of state 3 and state 4 respiration, respiratory control ratios, and ADP/O ratios were not affected by vitamin E deficiency alone. However, iron uncoupled oxidative phosphorylation in vitamin E-deficient mitochondria, but not in controls. In vitamin E-deficient mitochondria, iron decreased ADP/O ratios and markedly stimulated state 4 respiration; iron had only a modest effect on these parameters in control mitochondria. Thus, vitamin E may have an important role in sustaining oxidative phosphorylation. Low concentrations of iron (2 to 5 microM) oxidized mitochondrial tocopherol that exists in two pools. The release of iron in brain may impair oxidative phosphorylation, which would be exacerbated by vitamin E deficiency. The results are important for understanding the pathogenesis of human brain disorders known to be associated with abnormalities in mitochondrial function as well as iron homeostasis (e.g., Parkinson's disease).     

Effects of vitamin E and carotenoid status on oxidative stress in health and disease. Evidence obtained from human intervention studies

Vitamin E and carotenoids are known to act as antioxidants both in vitro and in vivo. In this review we present a series of studies in healthy subjects and in patients who exhibit either acute or chronic oxidative stress. In the EU-Commission funded VITAGE project we investigated the status and effects of vitamin E and carotenoids on oxidative stress in 300 healthy volunteers. Depletion studies limiting dietary vitamin E or carotenoid intake to 25% of the dietary reference intakes and subsequent repletion by supplementation with either large doses of vitamin E or intermediate doses of carotenoids showed significant changes in ex vivo LDL oxidizability, total plasma peroxide concentrations and urinary 8-oxo-7,8-dihydro-2^′-deoxyguanosine excretion. Patients on chronic hemodialysis present with oxidative stress in the presence of normal vitamin E but impaired vitamin C status and, due to anemia, need to be treated with parenteral iron. We studied the effects of a single oral dose of vitamin E taken 6 h prior to intravenous infusion of 100 mg iron, which exceeded the iron-binding capacity of transferrin. Vitamin E significantly reduced and in combination with a single dose of vitamin C completely abrogated acute oxidative stress induced by the iron load. Patients with cystic fibrosis are exposed to chronic oxidative stress due to an overproduction of reactive oxygen species as a result of neutrophil-dominated lung inflammation and impaired antioxidant status. Biochemical vitamin E and carotenoid deficiencies could be fully corrected even in the presence of fat malabsorption using intermediate doses of either RRR -tocopherol or all-rac -tocopheryl acetate and water-miscible all-trans β-carotene. Long-term supplementation reduced ex vivo LDL oxidizability, in vivo lipid peroxidation and lung inflammation.     

Vitamin E remains the major lipid-soluble, chain-breaking antioxidant in human plasma even in individuals suffering severe vitamin E deficiency

The chain-breaking (peroxyl radical-trapping) antioxidant activity of plasma obtained from several patients with a very severe vitamin E deficiency has been measured. The total chain-breaking antioxidant activity in lipid extracts has been shown to be approximately equal to the concentration of vitamin E. For whole plasma there is no significant difference in the concentrations of water-soluble, chain-breaking antioxidants between the E-deficient patients and healthy adults. It is concluded that even in cases of very severe vitamin E deficiency the requirement for this vitamin is not met by some other exogenous or endogenous antioxidant.     

Effect of Dietary Fat Quality and Vitamin E on the Antioxidant Potential of Pigs

A randomized blocked factorial experiment was conducted with 90 young pigs. From 4 to 11 weeks of age the pigs were kept in individual pens and fed a selenium supplemented basal diet consisting mostly of propionic acid treated barley, soybean meal and dried skim milk, and containing < 0.5 mg vitamin E per kg. The treatment factors during this period were 3 dietary levels of added vitamin E (nil, 10 and 30 mg/kg) and a 6 % supplement of fresh or oxidized fat (2/3 lard and 1/3 herring oil). From 11 weeks of age until slaughter at 90 kg the pigs received the vitamin E supplements but no fat or dried skim milk. The basal diet for this later experimental period was based on untreated dry barley. Blood samples collected during the period of investigation were examined for vitamin E and for resistance against erythrocyte lipid peroxidation (ELP) in order to evaluate the antioxidant status. Analysis of variance and Student’s t-test on least squares means showed the ELP to be influenced independently by the vitamin E supplement and, during the fat feeding period, by the quality of the fat supplement, with the highest peroxidation resistance (low ELP) in the groups fed fresh fat and a high level of vitamin E. Blood vitamin E level was only influenced — positively — by the vitamin E supplement although variations in the feed vitamin E level below 10–15 mg vitamin E per kg did not result in corresponding variations in measurable blood vitamin E concentrations. In the same low range of vitamin E in the feed there was a statistically significant difference in ELP values between the different vitamin E treatment groups. No clinical manifestations of selenium-vitamin E deficiency were observed in the pigs. The ELP and the plasma vitamin E levels observed would seem to suggest that a total of 15 mg vitamin E per kg barley-based feed will not always be sufficient for growing pigs.