High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice12345
| العنوان: | High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice12345 |
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| المؤلفون: | Christensen, Karen E, Mikael, Leonie G, Leung, Kit-Yi, Lévesque, Nancy, Deng, Liyuan, Wu, Qing, Malysheva, Olga V, Best, Ana, Caudill, Marie A, Greene, Nicholas DE, Rozen, Rima |
| المصدر: | The American Journal of Clinical Nutrition |
| بيانات النشر: | American Society for Nutrition, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Male, Mice, Inbred BALB C, Heterozygote, Lipogenesis, Gene-Nutrient Interactions, choline metabolism, Organ Size, liver, methylenetetrahydrofolate reductase, Methylation, digestive system diseases, Mice, Mutant Strains, Specific Pathogen-Free Organisms, folic acid, Gene Expression Regulation, Psychotic Disorders, Muscle Spasticity, Non-alcoholic Fatty Liver Disease, Dietary Supplements, Mutation, lipid metabolism, Animals, Homocystinuria, Enzyme Inhibitors, Methylenetetrahydrofolate Reductase (NADPH2) |
| الوصف: | Background: 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. Objective: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Design: 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. Results: 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 activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr+/− livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr+/− mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. Conclusions: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient. |
| اللغة: | English |
| تدمد: | 1938-3207 0002-9165 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=pmid________::072633c3cd72f82f057096674b8f23bdTest http://europepmc.org/articles/PMC4340065Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.pmid..........072633c3cd72f82f057096674b8f23bd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19383207 00029165 |
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