Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis

被引：37

作者：

Ganz, Ariel B. ^{[1
]}

Shields, Kelsey ^{[1
]}

Fomin, Vlad G. ^{[1
]}

Lopez, Yusnier S. ^{[1
]}

Mohan, Sanjay ^{[1
]}

Lovesky, Jessica ^{[1
]}

Chuang, Jasmine C. ^{[1
]}

Ganti, Anita ^{[1
]}

Carrier, Bradley ^{[1
]}

Yan, Jian ^{[1
]}

Taeswuan, Siraphat ^{[1
]}

Cohen, Vanessa V. ^{[1
]}

Swersky, Camille C. ^{[1
]}

Stover, Julie A. ^{[1
]}

Vitiello, Gerardo A. ^{[1
]}

Malysheva, Olga V. ^{[1
]}

Mudrak, Erika ^{[2
]}

Caudill, Marie A. ^{[1
]}

机构：

[1] Cornell Univ, Div Nutr Sci, 228 Savage Hall, Ithaca, NY 14850 USA

[2] Cornell Univ, Stat Consulting Unit, Ithaca, NY USA

来源：

FASEB JOURNAL | 2016年 / 30卷 / 10期

基金：

美国国家卫生研究院; 美国食品与农业研究所;

关键词：

nutrigenetics; single nucleotide polymorphisms; 1-carbon metabolism; pregnancy; lactation; HUMAN METHIONINE SYNTHASE; METHYLENETETRAHYDROFOLATE REDUCTASE; PLASMA HOMOCYSTEINE; CDNA CLONING; RISK-FACTOR; METABOLISM; ALTERS; POLYMORPHISMS; VARIANT; IDENTIFICATION;

D O I：

10.1096/fj.201500138RR

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Although single nucleotide polymorphisms (SNPs) in folate-mediated pathways predict susceptibility to choline deficiency during severe choline deprivation, it is unknown if effects persist at recommended intakes. Thus, we used stable isotope liquid chromatography-mass spectrometry (LC-MS) methodology to examine the impact of candidate SNPs on choline metabolism in a long-term, randomized, controlled feeding trial among pregnant, lactating, and nonpregnant (NP) women consuming 480 or 930 mg/d choline (22% as choline-d(9), with d(9) indicating a deuterated trimethyl amine group) and meeting folate-intake recommendations. Variants impairing folate metabolism, methylenetetrahydrofolate reductase (MTHFR) rs1801133, methionine synthase (MTR) rs1805087 [wild-type (WT)], MTR reductase (MTRR) rs1801394, and methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (MTHFD1) rs2236225, influenced choline dynamics, frequently through interactions with reproductive state and choline intake, with fewer genotypic alterations observed among pregnant women. Women with these variants partitioned more dietary choline toward phosphatidylcholine (PC) biosynthesis via the cytidine diphosphate (CDP)-choline pathway at the expense of betaine synthesis even when use of betaine as a methyl donor was increased. Choline intakes of 930 mg/d restored partitioning of dietary choline between betaine and CDP-PC among NP (MTHFR rs1801133 and MTR rs1805087 WT) and lactating (MTHFD1 rs2236225) women with risk genotypes. Overall, our findings indicate that loss-of-function variants in folate-metabolizing enzymes strain cellular PC production, possibly via impaired folate-dependent phosphatidylethanolamine-N-methyltransferase (PEMT)-PC synthesis, and suggest that women with these risk genotypes may benefit from choline intakes exceeding current recommendations.

引用

页码：3321 / 3333

页数：13

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