Novel insights on interactions between folate and lipid metabolism (original) (raw)
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The Journal of nutrition, 2008
Folate plays an important role in the pathogenesis of several chronic diseases by its potential ability to modulate DNA methylation. We hypothesized that the postweaning period might be a highly susceptible period to dietary folate intervention for DNA methylation patterning. We determined the effects of timing and duration of dietary folate intervention provided during the postweaning period on genomic DNA methylation in adult rat liver. In study 1, weanling rats were randomized to receive an amino acid-defined diet containing 0 (deficient), 2 (control), or 8 (supplemented) mg folic acid/kg until 8 wk of age, after which all the rats were fed the control diet until 30 wk of age. In study 2, weanling rats were fed the control diet until 8 wk of age and then randomized to receive the diet containing 0, 2, or 8 mg folic acid/kg until 30 wk of age. In study 3, weanling rats were randomized to receive these diets until 30 wk of age. Dietary folate deficiency, but not supplementation, pr...
Journal of Nutrition
Folate plays an important role in the pathogenesis of several chronic diseases by its potential ability to modulate DNA methylation. We hypothesized that the postweaning period might be a highly susceptible period to dietary folate intervention for DNA methylation patterning. We determined the effects of timing and duration of dietary folate intervention provided during the postweaning period on genomic DNA methylation in adult rat liver. In study 1, weanling rats were randomized to receive an amino acid-defined diet containing 0 (deficient), 2 (control), or 8 (supplemented) mg folic acid/kg until 8 wk of age, after which all the rats were fed the control diet until 30 wk of age. In study 2, weanling rats were fed the control diet until 8 wk of age and then randomized to receive the diet containing 0, 2, or 8 mg folic acid/kg until 30 wk of age. In study 3, weanling rats were randomized to receive these diets until 30 wk of age. Dietary folate deficiency, but not supplementation, provided during the postweaning period through childhood to puberty significantly increased genomic DNA methylation by 34-48% (P , 0.04) in rat liver that persisted into adulthood following a return to the control diet at puberty. In contrast, dietary folate deficiency or supplementation continually imposed at weaning or at puberty did not significantly affect genomic DNA methylation in adult rat liver. Our data suggest that early folate nutrition during postnatal development plays an important role in epigenetic programming that can have a permanent effect in adulthood. J. Nutr. 138: 703-709, 2008.
. Journal of Nutrition 132: 2444S-2449S, 2002
Convincing evidence links folate deficiency with colorectal cancer incidence. Currently, it is believed that folate deficiency affects DNA stability principally through two potential pathways. 5,10-Methylenetetrahydro-folate donates a methyl group to uracil, converting it to thymine, which is used for DNA synthesis and repair. If folate is limited, imbalances in the DNA precursor pool occur, and uracil may be misincorporated into DNA. Subsequent misincorporation and repair may lead to double strand breaks, chromosomal damage and cancer. Moreover, folate affects gene expression by regulating cellular S-adenosylmethionine (SAM) levels. 5-Methyltet-rahydrofolate serves as methyl donor in the remethylation of homocysteine to methionine, which in turn is converted to SAM. SAM methylates specific cytosines in DNA, and this regulates gene transcription. As a consequence of folate deficiency, cellular SAM is depleted, which in turn induces DNA hypomethylation and potentially induces proto-oncogene expression leading to cancer. Data from several model systems supporting these mechanisms are reviewed here. There is convincing evidence that folate modulates both DNA synthesis and repair and DNA hypomethylation with altered gene expression in vitro. The data from in vivo experiments in rodents is more difficult to interpret because of variations in the animal and experimental systems used and the influence of tissue specificity and folate metabolism. Most importantly, the confounding effects of nutrient-gene interactions, together with the identification of polymorphisms in key enzyme systems and the influence that these have on folate metabolism and DNA stability, must be considered when interpreting evidence from human studies. J. Nutr. 132: 2444S-2449S, 2002.
Methylation status in healthy subjects with normal and high serum folate concentration
Nutrition, 2008
We assessed the impact of high serum folate concentration on erythrocyte Sadenosylmethionine (SAM), S-adenosylhomocysteine (SAH) concentrations, SAM/SAH ratio, CpG methylation levels across the promoter region of the extracellular superoxide dismutase (ec-SOD) gene, and ec-SOD activity in healthy men. Methods: Serum folate levels were measured in 111 subjects who were categorized in quintiles according to their folate status. Subjects located at the lowest, middle, and upper quintiles were selected for assessment of SAM and SAH by high-performance liquid chromatography, C677T genotype of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, ec-SOD methylation of CpG sites in lymphocytes genomic DNA by bisulfate treatment, and ec-SOD activity by a chemical assay. Results: Sixteen subjects were in the lowest serum folate quintile (Ͻ23.6 nmol/L), 17 in the middle (Ͼ34 -Ͻ42 nmol/L), and 14 in the highest (Ͼ45nmol/L). SAM concentration was higher in the upper than in the middle and lowest quintiles (5.57 Ϯ 1.58, 2.52 Ϯ 0.97, 2.29 Ϯ 1.2 mol/L; P Ͻ 0.0001). SAH concentration was higher in the upper compared with the lowest quintile (0.76 Ϯ 0.24 versus 0.52 Ϯ 0.23 mol/L, P Ͻ 0.001). There were no differences in the SAM/SAH ratio, ec-SOD activity, methylation status of CpG sites of the ec-SOD gene, and TMTHFR C677T genotype between groups. Conclusion: Serum folate concentrations in the highest quintile among healthy humans are associated with increased erythrocyte SAM and SAH concentrations, but not with SAM/SAH ratio or with methylation levels of CpG sites across the promoter region of the ec-SOD gene. Further research is required to determine if these findings are beneficial or harmful.
Molecules
Folate (vitamin B9) is involved in one-carbon transfer reactions and plays a significant role in nucleic acid synthesis and control of cellular proliferation, among other key cellular processes. It is now recognized that the role of folates in different stages of carcinogenesis is complex, and more research is needed to understand how folate reactions become dysregulated in cancers and the metabolic consequences that occur as a result. ALDH1L1 (cytosolic 10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism expressed in many tissues, is ubiquitously downregulated in cancers and is not expressed in cancer cell lines. The RT4 cell line (derived from papillary bladder cancer) which expresses high levels of ALDH1L1 represents an exception, providing an opportunity to explore the metabolic consequences of the loss of this enzyme. We have downregulated this protein in RT4 cells (shRNA driven knockdown or CRISPR driven knockout) and compared metabolomes of ALDH1L1-expres...
Molecular nutrition & food research, 2016
The 'Predictive Adaptive Response' hypothesis suggests the in utero environment when mismatched with the post-natal environment can influence later life health. Underlying mechanisms are poorly understood, but may involve gene transcription changes, regulated via epigenetic mechanisms. In a 2 × 2 factorial design, female C57Bl/6 mice were randomised to low or normal folate diets (0.4mg/2mg folic acid/kg diet) prior to and during pregnancy and lactation with offspring randomised to high or low fat diets at weaning. Genome-wide gene expression and promoter DNA methylation were measured using microarrays in adult male livers. Maternal folate depletion and high fat intake post-weaning influenced gene expression (1859 and 1532 genes respectively) and promoter DNA methylation (201 and 324 loci respectively) but changes in expression and methylation were poorly matched for both dietary interventions. Expression of 642 genes was altered in response to both maternal folate depletion ...
The American journal of clinical nutrition, 2015
Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Folic acid-supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr(+/+) and Mthfr(+/-) mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr(+/-) mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR a...
The American Journal of Clinical Nutrition, 2019
Background: Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans. Objective: The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes. Methods: A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes. Results: The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74