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Reduced MTHFD1 activity in male mice perturbs folate- and choline-dependent one-carbon metabolism as well as transsulfuration.

Impaired utilization of folate is caused by insufficient dietary intake and/or genetic variation and has been shown to prompt changes in related pathways, including choline and methionine metabolism. These pathways have been shown to be sensitive to variation within the Mthfd1 gene, which codes for... Full description

Journal Title: The Journal of nutrition January 2013, Vol.143(1), pp.41-45
Main Author: Field, Martha S
Other Authors: Shields, Kelsey S , Abarinov, Elena V , Malysheva, Olga V , Allen, Robert H , Stabler, Sally P , Ash, Jessica A , Strupp, Barbara J , Stover, Patrick J , Caudill, Marie A
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1541-6100 ; DOI: 10.3945/jn.112.169821
Link: http://search.proquest.com/docview/1273457680/?pq-origsite=primo
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title: Reduced MTHFD1 activity in male mice perturbs folate- and choline-dependent one-carbon metabolism as well as transsulfuration.
format: Article
creator:
  • Field, Martha S
  • Shields, Kelsey S
  • Abarinov, Elena V
  • Malysheva, Olga V
  • Allen, Robert H
  • Stabler, Sally P
  • Ash, Jessica A
  • Strupp, Barbara J
  • Stover, Patrick J
  • Caudill, Marie A
subjects:
  • Animals–Blood
  • Biomarkers–Metabolism
  • Choline–Blood
  • Cysteine–Metabolism
  • Disease Models, Animal–Blood
  • Folic Acid Deficiency–Metabolism
  • Heterozygote–Blood
  • Homocysteine–Enzymology
  • Isoenzymes–Metabolism
  • Liver–Blood
  • Male–Metabolism
  • Methionine–Genetics
  • Methylation–Metabolism
  • Methylenetetrahydrofolate Dehydrogenase (Nadp)–Enzymology
  • Mice–Metabolism
  • Mice, Inbred C57bl–Blood
  • Mice, Mutant Strains–Metabolism
  • Mutagenesis, Insertional–Genetics
  • Mutant Proteins–Metabolism
  • Random Allocation–Metabolism
  • Biomarkers
  • Isoenzymes
  • Mutant Proteins
  • Homocysteine
  • Methionine
  • Methylenetetrahydrofolate Dehydrogenase (Nadp)
  • Cysteine
  • Choline
ispartof: The Journal of nutrition, January 2013, Vol.143(1), pp.41-45
description: Impaired utilization of folate is caused by insufficient dietary intake and/or genetic variation and has been shown to prompt changes in related pathways, including choline and methionine metabolism. These pathways have been shown to be sensitive to variation within the Mthfd1 gene, which codes for a folate-metabolizing enzyme responsible for generating 1-carbon (1-C)-substituted folate derivatives. The [Mthfd1.sup.gt/+] mouse serves as a potential model of human Mthfd1 loss-of-function genetic variants that impair MTHFD1 function. This study investigated the effects of the [Mthfd1.sup.gt/+] genotype and folate intake on markers of choline, folate, methionine, and transsulfuration metabolism. Male [Mthfd1.sup.gt/+] and [Mthfd1.sup.+/+] mice were randomly assigned at weaning (3 wk of age) to either a control (2 mg/kg folic acid) or folate-deficient (0 mg/kg folic acid) diet for 5 wk. Mice were killed at 8 wk of age following 12 h of food deprivation; blood and liver samples were analyzed for choline, methionine, and transsulfuration biomarkers. Independent of folate intake, mice with the [Mthfd1.sup.gt/+] genotype had higher hepatic concentrations of choline (P = 0.005), betaine (P = 0.013), and dimethylglycine (P= 0.004) and lower hepatic concentrations of glycerophosphocholine (P = 0.002) relative to [Mthfd1.sup.+/+] mice. [Mthfd1.sup.+/+] mice also had higher plasma concentrations of homocysteine (P = 0.0016) and cysteine (P < 0.001) as well as lower plasma concentrations of methionine (P = 0.0003) and cystathionine (P = 0.011). The metabolic alterations observed in [Mthfd1.sup.gt/+] mice indicate perturbed choline and folate-dependent 1-C metabolism and support the future use of [Mthfd1.sup.gt/+] mice as a tool to investigate the impact of impaired 1-C metabolism on disease outcomes. doi: 10.3945/jn.112.169821
language: eng
source:
identifier: E-ISSN: 1541-6100 ; DOI: 10.3945/jn.112.169821
fulltext: fulltext
issn:
  • 15416100
  • 1541-6100
url: Link


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titleReduced MTHFD1 activity in male mice perturbs folate- and choline-dependent one-carbon metabolism as well as transsulfuration.
creatorField, Martha S ; Shields, Kelsey S ; Abarinov, Elena V ; Malysheva, Olga V ; Allen, Robert H ; Stabler, Sally P ; Ash, Jessica A ; Strupp, Barbara J ; Stover, Patrick J ; Caudill, Marie A
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ispartofThe Journal of nutrition, January 2013, Vol.143(1), pp.41-45
identifierE-ISSN: 1541-6100 ; DOI: 10.3945/jn.112.169821
subjectAnimals–Blood ; Biomarkers–Metabolism ; Choline–Blood ; Cysteine–Metabolism ; Disease Models, Animal–Blood ; Folic Acid Deficiency–Metabolism ; Heterozygote–Blood ; Homocysteine–Enzymology ; Isoenzymes–Metabolism ; Liver–Blood ; Male–Metabolism ; Methionine–Genetics ; Methylation–Metabolism ; Methylenetetrahydrofolate Dehydrogenase (Nadp)–Enzymology ; Mice–Metabolism ; Mice, Inbred C57bl–Blood ; Mice, Mutant Strains–Metabolism ; Mutagenesis, Insertional–Genetics ; Mutant Proteins–Metabolism ; Random Allocation–Metabolism ; Biomarkers ; Isoenzymes ; Mutant Proteins ; Homocysteine ; Methionine ; Methylenetetrahydrofolate Dehydrogenase (Nadp) ; Cysteine ; Choline
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descriptionImpaired utilization of folate is caused by insufficient dietary intake and/or genetic variation and has been shown to prompt changes in related pathways, including choline and methionine metabolism. These pathways have been shown to be sensitive to variation within the Mthfd1 gene, which codes for a folate-metabolizing enzyme responsible for generating 1-carbon (1-C)-substituted folate derivatives. The [Mthfd1.sup.gt/+] mouse serves as a potential model of human Mthfd1 loss-of-function genetic variants that impair MTHFD1 function. This study investigated the effects of the [Mthfd1.sup.gt/+] genotype and folate intake on markers of choline, folate, methionine, and transsulfuration metabolism. Male [Mthfd1.sup.gt/+] and [Mthfd1.sup.+/+] mice were randomly assigned at weaning (3 wk of age) to either a control (2 mg/kg folic acid) or folate-deficient (0 mg/kg folic acid) diet for 5 wk. Mice were killed at 8 wk of age following 12 h of food deprivation; blood and liver samples were analyzed for choline, methionine, and transsulfuration biomarkers. Independent of folate intake, mice with the [Mthfd1.sup.gt/+] genotype had higher hepatic concentrations of choline (P = 0.005), betaine (P = 0.013), and dimethylglycine (P= 0.004) and lower hepatic concentrations of glycerophosphocholine (P = 0.002) relative to [Mthfd1.sup.+/+] mice. [Mthfd1.sup.+/+] mice also had higher plasma concentrations of homocysteine (P = 0.0016) and cysteine (P < 0.001) as well as lower plasma concentrations of methionine (P = 0.0003) and cystathionine (P = 0.011). The metabolic alterations observed in [Mthfd1.sup.gt/+] mice indicate perturbed choline and folate-dependent 1-C metabolism and support the future use of [Mthfd1.sup.gt/+] mice as a tool to investigate the impact of impaired 1-C metabolism on disease outcomes. doi: 10.3945/jn.112.169821
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titleReduced MTHFD1 activity in male mice perturbs folate- and choline-dependent one-carbon metabolism as well as transsulfuration.
authorField, Martha S ; Shields, Kelsey S ; Abarinov, Elena V ; Malysheva, Olga V ; Allen, Robert H ; Stabler, Sally P ; Ash, Jessica A ; Strupp, Barbara J ; Stover, Patrick J ; Caudill, Marie A
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