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Folate intake, MTHFR genotype, and sex modulate choline metabolism in mice.

ABSTRACT: Choline and folate are interrelated in 1-carbon metabolism, mostly because of their shared function as methyl donors for homocysteine remethylation. Folate deficiency and mutations of methylenetetrahydrofolate reductase (MTHFR) reduce the availability of a major methyl donor, 5-methyltetrahydrofolate, which in turn may lead to compensatory changes in choline metabolism. This study investigated the hypothesis that reductions in methyl group supply, either due to dietary folate deficiency or Mthfr gene deletion, would modify tissue choline metabolism in a sex-specific manner. Mthfr wild type (+/+) or heterozygous (+/-) knockout mice were randomized to a folate-deficient or control diet for 8 wk during which time deuterium-labeled choline (d9-choline) was consumed in the drinking water (~10 ?mol/d). Mthfr heterozygosity did not alter brain choline metabolite concentrations, but it did enhance their labeling in males (P < 0.05) and tended to do so in females (P < 0.10), a finding consistent with greater turnover of dietary choline in brains of +/- mice. Dietary folate deficiency in females yielded 52% higher (P = 0.027) hepatic glycerophosphocholine, which suggests that phosphatidylcholine (PtdCho) degradation was enhanced. Labeling of the hepatic PtdCho in d3 form was also reduced (P < 0.001) in females, which implies that fewer of the dietary choline-derived methyl groups were used for de novo PtdCho biosynthesis under conditions of folate insufficiency. Males responded to folate restriction with a doubling (P < 0.001) of hepatic choline dehydrogenase transcripts, a finding consistent with enhanced conversion of choline to the methyl donor, betaine. Collectively, these data show that several adaptations in choline metabolism transpire as a result of mild perturbations in folate metabolism, presumably to preserve methyl group homeostasis.

SUBMITTER: Chew TW

PROVIDER: S-EPMC3138639 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Folate intake, MTHFR genotype, and sex modulate choline metabolism in mice.

Chew Tina W TW Jiang Xinyin X Yan Jian J Wang Wei W Lusa Amanda L AL Carrier Bradley J BJ West Allyson A AA Malysheva Olga V OV Brenna J Thomas JT Gregory Jesse F JF Caudill Marie A MA

The Journal of nutrition 20110622 8

Choline and folate are interrelated in 1-carbon metabolism, mostly because of their shared function as methyl donors for homocysteine remethylation. Folate deficiency and mutations of methylenetetrahydrofolate reductase (MTHFR) reduce the availability of a major methyl donor, 5-methyltetrahydrofolate, which in turn may lead to compensatory changes in choline metabolism. This study investigated the hypothesis that reductions in methyl group supply, either due to dietary folate deficiency or Mthfr ...[more]

PMID: 21697299

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Project description:BackgroundThe etiology of postpartum psychopathologies are not well understood, but folate metabolism pathways are of potential interest. Demands for folate increase dramatically during pregnancy, low folate level has been associated with psychiatric disorders, and supplementation may improve symptomatology. The MTHFR C677T variant influences folate metabolism and has been implicated in depression during pregnancy.ObjectiveTo conduct a prospective longitudinal study to explore the relationship between MTHFR C677T genotype, folate levels, and postpartum psychopathology in at-risk women.HypothesisIn the first three months postpartum, folate will moderate a relationship between MTHFR genotype and depression, with TT homozygous women having more symptoms than CC homozygous women.MethodsWe recruited 365 pregnant women with a history of mood or psychotic disorder, and at 3 postpartum timepoints, administered the Edinburgh Postnatal Depression Scale (EPDS); Clinician-Administered Rating Scale for Mania (CARS-M) and the Positive and Negative Symptom Scale (PANSS) and drew blood for genotype/folate level analysis. We used robust linear regression to investigate interactions between genotype and folate level on the highest EPDS and CARS-M scores, and logistic regression to explore interactions with PANSS psychosis scores above/below cut-off.ResultsThere was no significant interaction effect between MTHFR genotype and folate level on highest EPDS (p = 0.36), but there was a significant interaction between genotype, folate level and log(CARS-M) (p = 0.02); post-hoc analyses revealed differences in the effect of folate level between CC/CT, and TT genotypes, with folate level in CC and CT having an inverse relationship with symptoms of mania, while there was no relationship in participants with TT genotype. There was no significant interaction between MTHFR genotype and folate level on the likelihood of meeting positive symptom criteria for psychosis on the PANSS (p = 0.86).DiscussionThese data suggest that perhaps there is a relationship between MTHFR C677T, folate level and some symptoms of postpartum psychopathology.

Dataset Information

Folate intake, MTHFR genotype, and sex modulate choline metabolism in mice.

Publications

Folate intake, MTHFR genotype, and sex modulate choline metabolism in mice.

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