Choline is a dietary nutrient essential for the structural integrity and signaling functions of cell membranes;it is the major source of methyl-groups in the diet, and it directly affects cholinergic neurotransmission, transmembrane signaling and lipid transport/metabolism. The major premise for this proposal is that humans require a dietary source of choline and that this requirement has significant individual variation. We suggest that estrogen and common genetic polymorphisms modulate this dietary requirement for choline. During the last 4 years of funding we established that 77% of men and 80% of postmenopausal women, when deprived of dietary choline, developed fatty liver or muscle damage. Only 43% of premenopausal women developed signs of organ dysfunction associated with choline deficiency. Some men developed such signs of choline deficiency when ingesting the presumed Adequate Intake for choline (550 mg/day). We observed that the PEMT promoter is estrogen responsive, and we hypothesize that estrogen status influences the dietary requirement for choline. We identified common genetic variations that appear to increase the likelihood that a human will become choline deficient when fed a low choline diet;postmenopausal women with a common single nucleotide polymorphism (snp) in the promoter region of the gene responsible for endogenous biosynthesis of choline (phosphatidylethanolamine N-methyltransferase, PEMT;rs12325817) had a odds ratio (OR) compared to wild type of 42 for developing signs of organ dysfunction when we removed choline from their diets (p=0.03);premenopausal women with a G78T snp in choline dehydrogenase had an OR of 20 (p=0.04) and premenopausal women with a common snp in methylene tetrahydrofolate dehydrogenase (MTHFD1-1958A) had an OR of >85 (p=.0001) for developing signs of choline deficiency. We identified another snp in choline dehydrogenase A40 that was associated with a decreased susceptibility to developing signs of choline deficiency in all subjects (OR = 0.2;p = 0.03). These snps are common in humans, for example, for the PEMT promoter snp 18% of our subjects were homozygous for the snp, 56% were heterozygous, and 26% were wild type. Therefore, it is important that we have a better understanding of how these genetic polymorphisms influence the dietary requirement for choline. We propose studies that will extend our observations during the last funding period and that will refine our understanding of factors that influence dietary requirements for choline in humans. Experiments are proposed that will determine whether postmenopausal women treated with estrogen have a lower choline requirement, identify functionally important SNPs, determine prevalence of these in the population and examine dietary choline requirements in humans with these SNPs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055865-09
Application #
7759577
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (04))
Program Officer
Maruvada, Padma
Project Start
2000-09-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
9
Fiscal Year
2010
Total Cost
$747,307
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Nutrition
Type
Schools of Public Health
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
da Costa, Kerry-Ann; Corbin, Karen D; Niculescu, Mihai D et al. (2014) Identification of new genetic polymorphisms that alter the dietary requirement for choline and vary in their distribution across ethnic and racial groups. FASEB J 28:2970-8
Zeisel, Steven H (2013) Metabolic crosstalk between choline/1-carbon metabolism and energy homeostasis. Clin Chem Lab Med 51:467-75
Du, Xiuxia; Zeisel, Steven H (2013) Spectral deconvolution for gas chromatography mass spectrometry-based metabolomics: current status and future perspectives. Comput Struct Biotechnol J 4:e201301013
Zeisel, Steven H; Waterland, Robert A; Ordovas, Jose M et al. (2013) Highlights of the 2012 Research Workshop: Using nutrigenomics and metabolomics in clinical nutrition research. JPEN J Parenter Enteral Nutr 37:190-200
Corbin, Karen D; Abdelmalek, Manal F; Spencer, Melanie D et al. (2013) Genetic signatures in choline and 1-carbon metabolism are associated with the severity of hepatic steatosis. FASEB J 27:1674-89
Mehedint, Mihai G; Zeisel, Steven H (2013) Choline's role in maintaining liver function: new evidence for epigenetic mechanisms. Curr Opin Clin Nutr Metab Care 16:339-45
Johnson, Amy R; Lao, Sai; Wang, Tongwen et al. (2012) Choline dehydrogenase polymorphism rs12676 is a functional variation and is associated with changes in human sperm cell function. PLoS One 7:e36047
Zeisel, Steven H (2012) A brief history of choline. Ann Nutr Metab 61:254-8
Teng, Ya-Wen; Ellis, Jessica M; Coleman, Rosalind A et al. (2012) Mouse betaine-homocysteine S-methyltransferase deficiency reduces body fat via increasing energy expenditure and impairing lipid synthesis and enhancing glucose oxidation in white adipose tissue. J Biol Chem 287:16187-98
Cheatham, Carol L; Goldman, Barbara Davis; Fischer, Leslie M et al. (2012) Phosphatidylcholine supplementation in pregnant women consuming moderate-choline diets does not enhance infant cognitive function: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 96:1465-72

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