Dataset Information

Aberrant estrogen regulation of PEMT results in choline deficiency-associated liver dysfunction.

ABSTRACT: When dietary choline is restricted, most men and postmenopausal women develop multiorgan dysfunction marked by hepatic steatosis (choline deficiency syndrome (CDS)). However, a significant subset of premenopausal women is protected from CDS. Because hepatic PEMT (phosphatidylethanolamine N-methyltransferase) catalyzes de novo biosynthesis of choline and this gene is under estrogenic control, we hypothesized that there are SNPs in PEMT that disrupt the hormonal regulation of PEMT and thereby put women at risk for CDS. In this study, we performed transcript-specific gene expression analysis, which revealed that estrogen regulates PEMT in an isoform-specific fashion. Locus-wide SNP analysis identified a risk-associated haplotype that was selectively associated with loss of hormonal activation. Chromatin immunoprecipitation, analyzed by locus-wide microarray studies, comprehensively identified regions of estrogen receptor binding in PEMT. The polymorphism (rs12325817) most highly linked with the development of CDS (p < 0.00006) was located within 1 kb of the critical estrogen response element. The risk allele failed to bind either the estrogen receptor or the pioneer factor FOXA1. These data demonstrate that allele-specific ablation of estrogen receptor-DNA interaction in the PEMT locus prevents hormone-inducible PEMT expression, conferring risk of CDS in women.

SUBMITTER: Resseguie ME

PROVIDER: S-EPMC3020773 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Aberrant estrogen regulation of PEMT results in choline deficiency-associated liver dysfunction.

Resseguie Mary E ME da Costa Kerry-Ann KA Galanko Joseph A JA Patel Mukund M Davis Ian J IJ Zeisel Steven H SH

The Journal of biological chemistry 20101108 2

When dietary choline is restricted, most men and postmenopausal women develop multiorgan dysfunction marked by hepatic steatosis (choline deficiency syndrome (CDS)). However, a significant subset of premenopausal women is protected from CDS. Because hepatic PEMT (phosphatidylethanolamine N-methyltransferase) catalyzes de novo biosynthesis of choline and this gene is under estrogenic control, we hypothesized that there are SNPs in PEMT that disrupt the hormonal regulation of PEMT and thereby put ...[more]

PMID: 21059658

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Project description:Abstract Objectives Choline-metabolizing genetic variation may interact with choline intake on fetal programming and pregnancy outcome. This case-control study aims to explore the association of maternal choline consumption and phosphatidylethanolamine N-methyltransferase (PEMT) gene polymorphism rs7946 with incident preterm birth. Methods 165 Chinese Han women with preterm delivery and 165 Chinese Han women with term delivery were recruited in Shanghai, China. Dietary choline intake during pregnancy was assessed using a validated food frequency questionnaire. Additionally, DNA samples were genotyped for PEMT rs7946 (G5465A) by a real-time polymerase chain reaction method with plasma homocysteine (Hcy) levels measured by an enzymatic cycling method. Odds ratio (OR) and 95% CI were estimated using unconditional logistic regression with adjustment of the covariates which were selected based on a comparison of social-democratic and clinical characteristics between two groups. Results There was a significant interaction between maternal choline intake and PEMT rs7946 (P for interaction = 0.04), where the AA genotype carriers who consumed the energy-adjusted choline <255.01 mg/d had an adjusted OR for preterm birth of 3.75 (95% CI 1.24–11.35), compared to those with GG genotype and choline intake >255.01 mg/d during pregnancy. Additionally, the highest plasma Hcy was found in the cases with AA genotype and choline consumption <255.01 mg/d (P < 0.001). The AA genotype was also associated with a greater risk of preterm birth among the women when their plasma Hcy is at the highest tertile level (AA vs. GA + GG: adjusted OR = 1.56, 95% CI 1.02–2.88). Conclusions The AA genotype of PEMT rs7946 may be associated with increased preterm birth in these Chinese Han women with low choline intake during pregnancy. The observed association may be partially explained by mechanisms related to the increasing Hcy level induced by PEMT rs7946 gene polymorphism. This study was registered at ClinicalTrials.gov (#NCT02841813). Funding Sources The Danone Nutrition Research and Education Grant (DIC2017–09); Research Project of Shanghai University of Traditional Chinese Medicine (2019LK042).

Dataset Information

Aberrant estrogen regulation of PEMT results in choline deficiency-associated liver dysfunction.

Publications

Aberrant estrogen regulation of PEMT results in choline deficiency-associated liver dysfunction.

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