Novel function of vitamin E in regulation of zebrafish (Danio rerio) brain lysophospholipids discovered using lipidomics

Abstract

This article is available online at http://www.jlr.org have used zebrafi sh to characterize the molecular consequences of vitamin E defi ciency because zebrafi sh require dietary ␣ -tocopherol, especially during embryonic development ( 2 ). Zebrafi sh also express the ␣ -tocopherol transfer protein ( ␣ -TTP), which facilitates hepatic ␣ -tocopherol secretion into the circulation in humans ( 3 ), and likely facilitates ␣ -tocopherol delivery from the yolk to the developing zebrafi sh embryo ( 4 ). Importantly, when the ␣ -TTP was knocked down in zebrafi sh embryos by 12-15 h postfertilization, the embryonic brain and eyes failed to form appropriately ( 4 ), indicating that ␣ -tocopherol is necessary for nervous system development. Further, during embryonic growth over 72 h both DHA (22:6) and arachidonic acid (AA) (20:4) decreased at faster rates in vitamin E-defi cient (E Ϫ ) compared with vitamin E-suffi cient (E+) zebrafi sh embryos ( 5 ). Moreover, adequate dietary ascorbic acid was necessary to prevent accelerated ␣ -tocopherol defi ciency and tissue damage ( 5 ).We hypothesized that the devastating effects of severe ␣ -tocopherol defi ciency in zebrafi sh embryos ( 4 ) are a result of depletion and alteration of critical brain lipids. Hypothetically, the brain, which is highly enriched in DHA yet cannot synthesize DHA to meet its needs ( 6 ), is highly susceptible to lipid peroxidation in the ␣ -tocopheroldefi cient state. It has been recognized for decades in humans that vitamin E defi ciency causes a progressive spinocerebellar ataxia ( 7 ). Moreover, Ulatowski et al. ( 8 ) have shown that vitamin E is necessary for preservation of Abstract We hypothesized that brains from vitamin E-defi cient (E ؊ ) zebrafi sh ( Danio rerio ) would undergo increased lipid peroxidation because they contain highly polyunsaturated fatty acids, thus susceptible lipids could be identifi ed. Brains from zebrafi sh fed for 9 months defi ned diets without (E ؊ ) or with (E+) added vitamin E (500 mg RRR -␣ -tocopheryl acetate per kilogram diet) were studied. Using an untargeted approach, 1-hexadecanoyl-2-docosahexaenoyl-sn -glycero-3-phosphocholine [DHA-PC 38:6, PC 16:0/22:6]was the lipid that showed the most signifi cant and greatest fold-differences between groups. DHA-PC concentrations were approximately 1/3 lower in E ؊ (4.3 ± 0.6 mg/g) compared with E+ brains (6.5 ± 0.9 mg/g, mean ± SEM, n = 10 per group, P = 0.04). Using lipidomics, 155 lipids in brain extracts were identifi ed. Only four phospholipids (PLs) were different ( P < 0.05) between groups; they were lower in E ؊ brains and contained DHA with DHA-PC 38:6 at the highest abundances. Moreover, hydroxy-DHA-PC 38:6 was increased in E ؊ brains ( P = 0.0341) supporting the hypothesis of DHA peroxidation. More striking was the depletion in E ؊ brains of nearly 60% of 19 different lysophospholipids (lysoPLs) (combined P = 0.0003), which are critical for membrane PL remodeling. Thus, E ؊ brains contained fewer DHA-PLs, more hydroxy-DHA-PCs, and fewer lysoPLs, suggesting t...

Chronic vitamin E deficiency impairs cognitive function in adult zebrafish via dysregulation of brain lipids and energy metabolism

“…Lipidomics data processing was performed as described [23,25]. Student’s t -tests (Excel, Microsoft) were used to compare the two VitE groups with statistical significance set at p < 0.05.…”

“…These combined antioxidant deficiencies precluded assessment of neurological and cognitive consequences resulting solely from VitE deficiency. Therefore, in the present study, we investigated the behavioral perturbations of isolated VitE deficiency in adult E− and E+ zebrafish fed diets with adequate ascorbic acid [22,23]. We hypothesized that E− adult zebrafish would display significant cognitive impairments associated with elevated brain lipid peroxidation and, potentially, additional metabolic disruptions, as we reported in VitE-deficient zebrafish embryos [24,25].…”

Lipidomics in translational research and the clinical significance of lipid-based biomarkers

“…For example, Choi and co-workers found that low vitamin E concentrations are correlated with a ~60% depletion of 4 DHA-containing phospholipids and 19 lyso phospholipids in zebra fish brains. Due to the decrease of DHA-containing phospholipids in Vitamin E-deficient zebra fish, vitamin E is postulated to play a role in the homeostatic balance of anti-inflammatory and inflammatory lipids in the brain (98). …”

From Epidemiology to Epigenetics: Evidence for the Importance of Nutrition to Optimal Health Development Across the Life Course

“…Although supplements have been found to have benefit in slowing Alzheimer's disease progression, they do not seem to prevent Alzheimer's disease occurrence (Traber 2014). Because 96% of adult women and 90% of men in the United States do not receive adequate levels of vitamin E in their diet (Choi et al 2015), it would seem that additional studies are needed to explore further risk reduction related to the development of cognitive impairment.…”

“…In a prospective study carried out in Finland, a sample of 140 over 65-year-olds with no memory impairment at the onset of the study was followed for 8 years, during which time it was found that higher total serum levels of vitamin E (alpha-tocopherol), as well as the other forms of the vitamin, seemed protective against memory disorders (Mangialasche et al 2013). A recent study, using a zebra fish model, showed that a diet deficient in vitamin E-equivalent to a human lifelong deficiency-resulted in about 30% lower levels of DHA phosphatidylcholine (DHA-PC), which is a part of the cellular membrane in every brain cell or neuron, indicating that DHA-PC may be a good predictor of a higher risk for Alzheimer's disease (Choi et al 2015). A recent meta-analysis found that patients with Alzheimer's disease, compared with cognitively intact elderly controls, had significantly lower plasma alphatocopherol concentrations (Lopes da Silva et al 2013).…”