Vitamin E (Alpha-Tocopherol) Metabolism and Nutrition in Chronic Kidney Disease

Francesco Galli, Mario Bonomini, Desirée Bartolini, Linda Zatini, Gianpaolo Reboldi, Giada Marcantonini, Giorgio Gentile, Vittorio Sirolli, Natalia Di Pietro

Antioxidants (Basel) . 2022 May 18;11(5):989. doi: 10.3390/antiox11050989

Abstract

Vitamin E (alpha-tocopherol) is an essential micronutrient and fat-soluble antioxidant with proposed role in protecting tissues from uncontrolled lipid peroxidation. This vitamin has also important protein function and gene modulation effects. The metabolism of vitamin E depends on hepatic binding proteins that selectively retain food alpha-tocopherol for incorporation into nascent VLDL and tissue distribution together with esterified cholesterol and triglycerides. Chronic kidney disease (CKD) is a condition of oxidative stress and increased lipid peroxidation, that are associated with alterations of alpha-tocopherol metabolism and function. Specific changes have been reported for the levels of its enzymatic metabolites, including both short-chain and long-chain metabolites, the latter being endowed with regulatory functions on enzymatic and gene expression processes important for the metabolism of lipids and xenobiotics detoxification, as well as for the control of immune and inflammatory processes. Vitamin E therapy has been investigated in CKD using both oral vitamin E protocols and vitamin E-coated hemodialyzers, showing promising results in the secondary prevention of cardiovascular disease, as well as of immune and hematological complications. These therapeutic approaches are reviewed in the present article, together with a narrative excursus on the main findings indicating CKD as a condition of relative deficiency and impaired metabolism of vitamin E.

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Antioxidant effects of vitamin E and risk of cardiovascular disease in women with obesity – A narrative review

Anna Maria Rychter, Szymon Hryhorowicz, Ryszard Słomski, Agnieszka Dobrowolska, Iwona Krela-Kaźmierczak

Clin Nutr . 2022 May 6;41(7):1557-1565. doi: 10.1016/j.clnu.2022.04.032. Online ahead of print.

Abstract

Proper dietary habits are a vital element of cardiovascular (CV) treatment, and – according to the current guidelines – a diet rich in antioxidants is generally recommended. It remains, however, inconclusive whether antioxidant nutrients should be supplemented for CV health, and if so, in which form and dosage. Currently available data suggest that vitamin E may be essential in preventing CVD, especially in coronary heart disease and atherosclerosis – nevertheless, vitamin E supplementation may be questionable and may even be associated with adverse outcomes. Further, current studies highlight a strong need for identifying sex-specific strategies, which could improve guidelines for both the prevention and management of cardiovascular disease (CVD). It should also be emphasized that understanding the role of genetic variants in genes involved in VE metabolism may also be crucial for more precise nutritional recommendations for patients suffering from CVD. Therefore, we summarize the current knowledge regarding vitamin E antioxidant properties, which could be essential from CV perspective, and aim to assess whether vitamin E supplementation can be beneficial in CV prevention, especially in the high-risk group of women with obesity.

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Tocotrienols Attenuate White Adipose Tissue Accumulation and Improve Serum Cholesterol Concentration in High-Fat Diet-Treated Mice

Yugo Kato, Yoshinori Aoki, Chikako Kiyose, Koji Fukui

Molecules . 2022 Mar 28;27(7):2188. doi: 10.3390/molecules27072188.

Abstract

Tocotrienols (T3s), which are vitamin E homologs, have not only antioxidant function but also inhibitory effects on body weight gain and hepatic lipid droplet accumulation. However, the mechanisms of the anti-obesity effects of T3s are not yet understood. In this study, C57BL/6 mice were fed a high-fat diet in the presence or absence of T3s. Treatment with T3s inhibited white adipose tissue accumulation and elevation of serum cholesterol concentrations. Additionally, to clarify the relationship between obesity-induced cognitive dysfunction and the neuroprotective effect of T3s, cognitive function, brain oxidation, and protein expression levels of brain-derived neurotrophic factor (BDNF), which is strongly involved in neuronal growth and differentiation, were measured. Although mice behaviors were improved by oral T3 intake, there were no significant differences in brain oxidation levels and BDNF expression. These results suggest that T3s attenuate obesity via inhibition of body fat and serum cholesterol increase.

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Potential of the Compounds from Bixa orellana Purified Annatto Oil and Its Granules (Chronic ®) against Dyslipidemia and Inflammatory Diseases: In Silico Studies with Geranylgeraniol and Tocotrienols

Mateus Alves Batista, Abrahão Victor Tavares de Lima Teixeira Dos Santos, Aline Lopes do Nascimento, Luiz Fernando Moreira, Indira Ramos Senna Souza, Heitor Ribeiro da Silva, Arlindo César Matias Pereira, Lorane Izabel da Silva Hage-Melim, José Carlos Tavares Carvalho

Molecules . 2022 Feb 28;27(5):1584. doi: 10.3390/molecules27051584.

Abstract

Some significant compounds present in annatto are geranylgeraniol and tocotrienols. These compounds have beneficial effects against hyperlipidemia and chronic diseases, where oxidative stress and inflammation are present, but the exact mechanism of action of such activities is still a subject of research. This study aimed to evaluate possible mechanisms of action that could be underlying the activities of these molecules. For this, in silico approaches such as ligand topology (PASS and SEA servers) and molecular docking with the software GOLD were used. Additionally, we screened some pharmacokinetic and toxicological parameters using the servers PreADMET, SwissADME, and ProTox-II. The results corroborate the antidyslipidemia and anti-inflammatory activities of geranylgeraniol and tocotrienols. Notably, some new mechanisms of action were predicted to be potentially underlying the activities of these compounds, including inhibition of squalene monooxygenase, lanosterol synthase, and phospholipase A2. These results give new insight into new mechanisms of action involved in these molecules from annatto and Chronic®.

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Associations of metabolomic profiles with circulating vitamin E and urinary vitamin E metabolites in middle-aged individuals

Jiao Luo, Yasufumi Hashimoto, Leon G Martens, Fleur L Meulmeester, Nadia Ashrafi, Dennis O Mook-Kanamori, Frits R Rosendaal, J Wouter Jukema, Ko Willems van Dijk, Kevin Mills, Saskia le Cessie, Raymond Noordam, Diana van Heemst

Nutrition . 2021 Jul 29;93:111440. doi: 10.1016/j.nut.2021.111440. Online ahead of print.

Abstract

Vitamin E (α-tocopherol [α-TOH]) is transported in lipoprotein particles in blood, but little is known about the transportation of its oxidized metabolites. In the Netherlands Epidemiology of Obesity Study, we aimed to investigate the associations of 147 circulating metabolomic measures obtained through targeted nuclear magnetic resonance with serum α-TOH and its urinary enzymatic (α-CEHC) and oxidized (α-TLHQ) metabolites from 24-h urine quantified by liquid chromatography with tandem mass spectrometry. Multivariable linear regression analyses, in which multiple testing was taken into account, were performed to assess associations between metabolomic measures (determinants; standardized to mean = 0, SD = 1) and vitamin E metabolites (outcomes), adjusted for demographic factors. We analyzed 474 individuals (55% women, 45% men) with a mean (SD) age of 55.7 (6.0) y. Out of 147 metabolomic measures, 106 were associated (P < 1.34 × 10-3) with serum α-TOH (median β [interquartile range] = 0.416 [0.383-0.466]), predominantly lipoproteins associated with higher α-TOH. The associations of metabolomic measures with urinary α-CEHC have directions similar to those with α-TOH, but effect sizes were smaller and non-significant (median β [interquartile range] = 0.065 [0.047-0.084]). However, associations of metabolomic measures with urinary α-TLHQ were markedly different from those with both serum α-TOH and urinary α-CEHC, with negative and small-to-null relations to most very-low-density lipoproteins and amino acids. Therefore, our results highlight the differences in the lipoproteins involved in the transportation of circulating α-TOH and oxidized vitamin E metabolites. This indicates that circulating α-TOH may be representative of the enzymatic but not the antioxidative function of vitamin E.

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Association between ApoE status, circulating vitamin A and vitamin E levels with dyslipidemia in aging Chinese adults

Xiaojun Ma, Yujie Guo, Pengfei Li, Jingjing Xu, Yanyan Gao, Xiuwen Ren, Nicholas Van Halm-Lutterodt, Linhong Yuan

Arch Med Res . 2021 May 3;S0188-4409(21)00113-2. doi: 10.1016/j.arcmed.2021.04.007. Online ahead of print.

Abstract

Background: The influence of ApoE or lipid-soluble vitamins on lipid profile has been well documented. However, the association between ApoE status, vitamin A (VA) and vitamin E (VE) with dyslipidemia has been seldom reported. The aim of the present study was to investigate the impact of ApoE status on circulating VA and VE in aging adults with dyslipidemia.

Methods: A total of 1754 Chinese aged 55-75 was recruited from community health centers. They were interviewed to obtain demographic information. Food frequency questionnaire (FFQ) was used to investigate daily food intakes of the participants. Fasting venous blood samples were taken and used for serum lipid profile measurement and ApoE genotyping. Serum VA and VE concentrations were determined by using high-performance liquid chromatography (HPLC).

Results: Serum VE and VA concentrations were circulating lipids and ApoE status dependent. Dyslipidemia subjects showed higher serum TC, TG, HDL-c/LDL-c ratio, VE and lipid-adjusted VE levels than normal subjects. ApoE genotype-dependent differences in serum lipid profile, VE and VA levels were observed in both normal and dyslipidemia subjects. The relationship between circulating VA with dyslipidemia is modifiable by lipid status.

Conclusion: Higher serum VE and lipid adjusted VE levels associated with increased risk of dyslipidemia in aging Chinese adults, especially in ApoE4 carriers. Large scale longitudinal study is required to determine the optimal circulating VE levels in the elderly based on different lipid profiles and ApoE status.

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Effect of Statin Therapy on the Plasma Concentrations of Retinol, Alpha-Tocopherol and Coenzyme Q10 in Children with Familial Hypercholesterolemia

Radosław Motkowski, Mateusz Maciejczyk, Marta Hryniewicka, Joanna Karpińska, Bożena Mikołuć

Cardiovasc Drugs Ther . 2020 Oct 14. doi: 10.1007/s10557-020-07091-w. Online ahead of print.

Abstract

Purpose: Familial hypercholesterolemia (FH) requires early treatment. However, statins, which are regarded the first-line therapy, have an influence on redox balance. Antioxidant vitamins are important for many metabolic processes in the developing body. There are few data available on the long-term safety of statin use in children. The aim of this study was to evaluate the influence of statin treatment in children with FH on plasma concentrations of antioxidant vitamins: retinol, alpha-tocopherol and coenzyme Q10.

Methods: The first study group consisted of 13 children aged 10-18 years treated with simvastatin for at least 6 months, and the second group comprised 13 age- and sex-matched children with hypercholesterolemia, in whom pharmacological treatment had not been applied yet. Analyses were performed using a high-performance liquid chromatograph coupled with a MS detector.

Results: The analysis did not reveal significant differences in the concentration of retinol, alpha-tocopherol or coenzyme Q10 between the studied groups. The adjustment of the concentrations of the vitamins to the cholesterol level also indicated no significant differences. We found no deficits in antioxidant vitamins in patients treated with statins, or any risk of adverse effects associated with an increase in their concentration.

Conclusion: There is no rationale for additional supplementation using antioxidant vitamins or modification of low-fat and low-cholesterol diet in pediatric patients treated with statins.

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The effects of tocotrienol supplementation on lipid profile: A meta-analysis of randomized controlled trials

Shuping Zuo, Guiping Wang, QuanLe Han, Hongling Xiao, Heitor O Santos, David Avelar Rodriguez, Vahid Khani, Jianlei Tang

Complement Ther Med . 2020 Aug;52:102450. doi: 10.1016/j.ctim.2020.102450. Epub 2020 May 25.

Abstract

Background & objective: Tocotrienol supplementation has been emerged as a potent candidate for the treatment of dyslipidemia. In the present study, a systematic review and meta-analysis of randomized controlled trials was performed with the aim of examining the effects of tocotrienol supplementation on the lipid profile.

Methods: Four databases (Scopus, PubMed/Medline, Web of Science and Embase) were used to accomplish the literature search up to November 2019. Clinical trials encompassing the impact of tocotrienol supplementation on lipid profile were extracted regardless of clinical condition, with studies included involving only adults patients.

Results: A total of 15 articles with 20 arms were eligible and included in the meta-analysis to estimate the pooled effect size. Overall results showed a significant effect of tocotrienol supplementation on increasing high-density lipoprotein cholesterol (HDL-C) levels (weight mean difference (WMD): 0.146 mmol/L, I2 = 85.9%) and a non-significant influence on total cholesterol (TC) (WMD: 0.010 mmol/L, I2 = 64.5%), low-density lipoprotein cholesterol (LDL-C) (WMD: 0.095 mmol/L, I2 = 87.4%), and triglycerides (TG) (WMD: -0.112 mmol/L, I2 = 67.4%) levels. Increment in HDL-C levels was significant greater for the tocotrienol dosage ≥ 200 mg/d (WMD: 0.202 mmol/L) and ≤8 weeks (WMD: 0.278 mmol/L). Moreover, studies that investigated tocotrienol dose ≥200 mg had no heterogeneity, while showing a significant decrease in TG levels (WMD: -0.177 mmol/L).

Conclusion: The present meta-analysis demonstrated that supplementing with tocotrienols does not decrease the concentrations of LDL-C, TC and TG. However, tocotrienol supplementation was considered a candidate for increasing HDL-C levels.

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Effect of High Fructose-Induced Metabolic Syndrome on Tissue Vitamin E and Lipid Peroxide Levels in Rats

Akira Kitagawa, Yoshiji Ohta, Koji Ohashi, Koji Yashiro, Kenji Fukuzawa

J Nutr Sci Vitaminol (Tokyo) . 2020;66(2):200-206. doi: 10.3177/jnsv.66.200.

Abstract

In the present study, we examined the effect of high fructose-induced metabolic syndrome (MetS) on tissue vitamin E and lipid peroxide (LPO) levels in rats. Feeding of a diet containing 60% fructose (HFD) to Wistar rats for 2, 4, and 6 wk caused week-dependent increases in HOMA-IR score and serum insulin, triglyceride, total cholesterol, and free fatty acid concentrations. Each week HFD feeding increased serum vitamin E concentration. Six-week HFD feeding reduced vitamin E status (the serum ratio of vitamin E/triglyceride+total cholesterol). Four- and 6-wk HFD feeding increased serum LPO concentration. Two-week HFD feeding increased liver, heart, kidney, and skeletal muscle (SM) vitamin E contents and decreased white adipose tissue (WAT) vitamin E content. Four- and 6-wk HFD feeding further reduced WAT vitamin E content without affecting the increased kidney and SM vitamin E contents. Six-week HFD feeding reduced the increased liver and heart vitamin E contents below the level of non-HFD feeding. Four-week HFD feeding increased heart and WAT LPO contents. Six-week HFD feeding increased liver LPO content and further increased heart and WAT LPO contents. Kidney and SM LPO contents remained unchanged. These results indicate that HFD-rats with early MetS have increased liver, kidney, heart, and SM vitamin E contents and decreased WAT vitamin E content under unchanged tissue LPO content and vitamin E status, while HFD-fed rats with progressed MetS have both decreased liver, heart, and WAT vitamin E contents under increased tissue LPO content and disrupted vitamin E status.

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High-throughput Profiling Reveals Perturbation of Endoplasmic Reticulum Stress-Related Genes in Atherosclerosis Induced by High-Cholesterol Diet and the Protective Role of Vitamin E

Perinur Bozaykut, Ruchan Ekren, Osman Ugur Sezerman, Vadim N Gladyshev, Nesrin Kartal Ozer

Biofactors . 2020 May 8. doi: 10.1002/biof.1635.

Abstract

Formation of atherosclerotic plaques, called atherogenesis, is a complex process affected by genetic and environmental factors. It was proposed that endoplasmic reticulum (ER) stress is an important factor in the pathogenesis of atherosclerosis and that vitamin E affects atherosclerotic plaque formation via its antioxidant properties. Here, we investigated ER stress-related molecular mechanisms in high-cholesterol diet (HCD, 2%)-induced atherosclerosis model and the role of vitamin E supplementation in it, beyond its antioxidant properties. The consequences of HCD and vitamin E supplementation were examined by determining protein levels of ER stress markers in aortic tissues. As vitamin E supplementation acts on several unfolded protein response (UPR) factors, it decreased ER stress induced by HCD. To elucidate the associated pathways, gene expression profiling was performed, revealing differentially expressed genes enriched in ER stress-related pathways such as the proteasome and the apoptosis pathways. We further assessed the proteasomal activity impaired by HCD in the aorta and showed that vitamin E reversed it to that of control animals. Overall, the study characterized the effects of HCD and vitamin E on ER stress-related gene expression, revealing the role of proteolytic systems during atherogenesis.

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