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The role of gender and genetic polymorphisms in de novo choline synthesis

Authors
Publisher
University of North Carolina at Chapel Hill. Library
Publication Date
Disciplines
  • Biology

Abstract

Choline is an essential nutrient for humans, though some of the requirement can be met by endogenous synthesis catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). The human PEMT gene encodes three unique transcripts, A (NM_148172), B (NM_007169), and C (NM_148173) which encode two different protein isoforms. PEMT I, encoded by transcript A, localizes to the endoplasmic reticulum whereas PEMT II, synthesized from transcripts B and C, is found primarily in the mitochondrial associated membrane and is functionally distinct from PEMT I. Studies in mammals indicate a connection between estrogen and protection against choline deficiency syndrome (CDS) but the nature of this interaction is not understood. Examining the entire PEMT locus by chromatin immunoprecipitation coupled to microarray (ChIP-chip), we identified several estrogen receptor-alpha (ER-[alpha]) enriched regions in the PEMT locus specifically implicating a critical regulatory region located in intron 1 of the A transcription start site, 7500 nucleotides (nt) upstream of the transcriptional start site of transcript B. We found that PEMT transcription was increased in a dose-dependent manner when primary mouse and human hepatocytes were treated with 17-[beta]-estradiol for 24 hours and this increased message was associated with an increase in protein expression and enzyme activity. ER-[alpha] regulation of the PEMT gene is transcript-specific, whereby estrogen binding results in an increase in transcripts B and C but not transcript A. We suggest that differences in dietary choline requirements occur between men and women because estrogen induces expression of the PEMT gene, allowing premenopausal women to make more choline endogenously. In humans, young women harboring a PEMT promoter SNP are 25X as likely to develop CDS as are non-carriers of this SNP. Here we demonstrate, in human hepatocytes, that a haploblock of SNPs within a key estrogen regulatory region in the PEMT gene disrupt ER-[alpha] DNA binding. Hepatocytes homozygous for the risk allele were not estrogen responsive. For the first time, we report a putative mechanism underlying the association of PEMT genetic variation and susceptibility to choline deficiency syndrome in women.

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