Journal of Inherited Metabolic Disease

, Volume 34, Issue 1, pp 3–15 | Cite as

Choline and betaine in health and disease

  • Per Magne Ueland
Homocysteine and B-Vitamin Metabolism


Choline is an essential nutrient, but is also formed by de novo synthesis. Choline and its derivatives serve as components of structural lipoproteins, blood and membrane lipids, and as a precursor of the neurotransmitter acetylcholine. Pre-and postnatal choline availability is important for neurodevelopment in rodents. Choline is oxidized to betaine that serves as an osmoregulator and is a substrate in the betaine–homocysteine methyltransferase reaction, which links choline and betaine to the folate-dependent one-carbon metabolism. Choline and betaine are important sources of one-carbon units, in particular, during folate deficiency. Choline or betaine supplementation in humans reduces concentration of total homocysteine (tHcy), and plasma betaine is a strong predictor of plasma tHcy in individuals with low plasma concentration of folate and other B vitamins (B2, B6, and B12) in combination TT genotype of the methylenetetrahydrofolate reductase 677 C->T polymorphism. The link to one-carbon metabolism and the recent availability of food composition data have motivated studies on choline and betaine as risk factors of chronic diseases previously studied in relation to folate and homocysteine status. High intake and plasma level of choline in the mother seems to afford reduced risk of neural tube defects. Intake of choline and betaine shows no consistent relation to cancer or cardiovascular risk or risk factors, whereas an unfavorable cardiovascular risk factor profile was associated with high choline and low betaine concentrations in plasma. Thus, choline and betaine showed opposite relations with key components of metabolic syndrome, suggesting a disruption of mitochondrial choline oxidation to betaine as part of the mitochondrial dysfunction in metabolic syndrome.


Choline Homocysteine Betaine Choline Intake Neural Tube Defect 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.







Phosphatidylethanolamine N-methyltransferase


Betaine-homocysteine methyltransferase


Total homocysteine

PML tHcy

Post-methionine-load tHcy


Nonalcoholic fatty liver disease


  1. Abdelmalek MF, Sanderson SO, Angulo P et al (2009) Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatology 50:1818–1826PubMedCrossRefGoogle Scholar
  2. Adamczyk M, Brashear RJ, Mattingly PG (2006) Choline concentration in normal blood donor and cardiac troponin-positive plasma samples. Clin Chem 52:2123–2124PubMedCrossRefGoogle Scholar
  3. Adeyemo O, Jeyakumar H (1993) Plasma progesterone, estradiol-17 beta and testosterone in maternal and cord blood, and maternal human chorionic gonadotropin at parturition. Afr J Med Med Sci 22:55–60PubMedGoogle Scholar
  4. Alfthan G, Tapani K, Nissinen K, Saarela J, Aro A (2004) The effect of low doses of betaine on plasma homocysteine in healthy volunteers. Br J Nutr 92:665–669PubMedCrossRefGoogle Scholar
  5. Allen RH, Stabler SP, Lindenbaum J (1993) Serum betaine, N, N-dimethylglycine and N-methylglycine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism. Metabolism 42:1448–1460PubMedCrossRefGoogle Scholar
  6. Alvarez XA, Laredo M, Corzo D et al (1997) Citicoline improves memory performance in elderly subjects. Methods Find Exp Clin Pharmacol 19:201–210PubMedGoogle Scholar
  7. Anas MK, Lee MB, Zhou C et al (2008) SIT1 is a betaine/proline transporter that is activated in mouse eggs after fertilization and functions until the 2-cell stage. Development 135:4123–4130PubMedCrossRefGoogle Scholar
  8. Apple FS, Wu AH, Mair J et al (2005) Future biomarkers for detection of ischemia and risk stratification in acute coronary syndrome. Clin Chem 51:810–824PubMedCrossRefGoogle Scholar
  9. Barak AJ, Tuma DJ (1983) Betaine, metabolic by-product or vital methylating agent? Life Sci 32:771–774PubMedCrossRefGoogle Scholar
  10. Barak AJ, Beckenhauer HC, Tuma DJ (1996) Betaine, ethanol, and the liver: a review. Alcohol 13:395–398PubMedCrossRefGoogle Scholar
  11. Barak AJ, Beckenhauer HC, Badakhsh S, Tuma DJ (1997) The effect of betaine in reversing alcoholic steatosis. Alcohol Clin Exp Res 21:1100–1102PubMedGoogle Scholar
  12. Barak AJ, Beckenhauer HC, Mailliard ME, Kharbanda KK, Tuma DJ (2003) Betaine lowers elevated S-adenosylhomocysteine levels in hepatocytes from ethanol-fed rats. J Nutr 133:2845–2848PubMedGoogle Scholar
  13. Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G (2007) Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. BMC Cardiovasc Disord 7:20PubMedCrossRefGoogle Scholar
  14. Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G (2009) Repeatability and measurement error in the assessment of choline and betaine dietary intake: the Atherosclerosis Risk in Communities (ARIC) study. Nutr J 8:14PubMedCrossRefGoogle Scholar
  15. Bjelland I, Tell GS, Vollset SE, Konstantinova SV, Ueland PM (2009) Choline in anxiety and depression: the Hordaland Health Study. Am J Clin Nutr 90:1056–1060PubMedCrossRefGoogle Scholar
  16. Blusztajn JK, Zeisel SH, Wurtman RJ (1985) Developmental changes in the activity of phosphatidylethanolamine N-methyltransferases in rat brain. Biochem J 232:505–511PubMedGoogle Scholar
  17. Body R, Griffith CA, Keevil B et al (2009) Choline for diagnosis and prognostication of acute coronary syndromes in the Emergency Department. Clin Chim Acta 404:89–94PubMedCrossRefGoogle Scholar
  18. Boyles AL, Billups AV, Deak KL et al (2006) Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. Environ Health Perspect 114:1547–1552PubMedCrossRefGoogle Scholar
  19. Braekke K, Ueland PM, Harsem NK, Karlsen A, Blomhoff R, Staff AC (2007) Homocysteine, cysteine, and related metabolites in maternal and fetal plasma in preeclampsia. Pediatr Res 62:319–324PubMedCrossRefGoogle Scholar
  20. Brinkman SD, Smith RC, Meyer JS et al (1982) Lecithin and memory training in suspected Alzheimer’s disease. J Gerontol 37:4–9PubMedGoogle Scholar
  21. Buchman AL, Dubin MD, Moukarzel AA et al (1995) Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology 22:1399–1403PubMedGoogle Scholar
  22. Burg MB, Ferraris JD (2008) Intracellular organic osmolytes: function and regulation. J Biol Chem 283:7309–7313PubMedCrossRefGoogle Scholar
  23. Chiuve SE, Giovannucci EL, Hankinson SE et al (2007) The association between betaine and choline intakes and the plasma concentrations of homocysteine in women. Am J Clin Nutr 86:1073–1081PubMedGoogle Scholar
  24. Cho E, Willett WC, Colditz GA et al (2007a) Dietary choline and betaine and the risk of distal colorectal adenoma in women. J Natl Cancer Inst 99:1224–1231PubMedCrossRefGoogle Scholar
  25. Cho E, Zeisel SH, Jacques P et al (2006) Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study. Am J Clin Nutr 83:905–911PubMedGoogle Scholar
  26. Cho EY, Holmes M, Hankinson SE, Willett WC (2007b) Nutrients involved in one-carbon metabolism and risk of breast cancer among premenopausal women. Cancer Epidemiol Biomarkers Prev 16:2787–2790PubMedCrossRefGoogle Scholar
  27. Christman JK, Sheikhnejad G, Dizik M, Abileah S, Wainfan E (1993) Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency. Carcinogenesis 14:551–557PubMedCrossRefGoogle Scholar
  28. Cohen BM, Renshaw PF, Stoll AL, Wurtman RJ, Yurgelun-Todd D, Babb SM (1995) Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectrocospy study. JAMA 274:902–907PubMedCrossRefGoogle Scholar
  29. Cornford EM, Braun LD, Oldendorf WH (1978) Carrier mediated blood-brain barrier transport of choline and certain choline analogs. J Neurochem 30:299–308PubMedCrossRefGoogle Scholar
  30. Cornford EM, Braun LD, Oldendorf WH (1982) Developmental modulations of blood-brain barrier permeability as an indicator of changing nutritional requirements in the brain. Pediatr Res 16:324–328PubMedCrossRefGoogle Scholar
  31. daCosta KA, Badea M, Fischer LM, Zeisel SH (2004) Elevated serum creatine phosphokinase in choline-deficient humans: mechanistic studies in C2C12 mouse myoblasts. Am J Clin Nutr 80:163–170Google Scholar
  32. da Costa KA, Gaffney CE, Fischer LM, Zeisel SH (2005) Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load. Am J Clin Nutr 81:440–444PubMedGoogle Scholar
  33. daCosta KA, Niculescu MD, Craciunescu CN, Fischer LM, Zeisel SH (2006) Choline deficiency increases lymphocyte apoptosis and DNA damage in humans. Am J Clin Nutr 84:88–94Google Scholar
  34. da Costa K-A, Kozyreva OG, Song J, Galanko JA, Fischer LM, Zeisel SH (2006) Common genetic polymorphisms affect the human requirement for the nutrient choline. Faseb J 20:1336–1344PubMedCrossRefGoogle Scholar
  35. Dalmeijer GW, Olthof MR, Verhoef P, Bots ML, van der Schouw YT (2007) Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women. Eur J Clin Nutr 62(3):386–394Google Scholar
  36. Danne O, Lueders C, Storm C, Frei U, Mockel M (2007) Whole blood choline and plasma choline in acute coronary syndromes: prognostic and pathophysiological implications. Clin Chim Acta 383:103–109PubMedCrossRefGoogle Scholar
  37. Delgado-Reyes CV, Garrow TA (2005) High sodium chloride intake decreases betaine-homocysteine S-methyltransferase expression in guinea pig liver and kidney. Am J Physiol Regul Integr Comp Physiol 288:R182–R187PubMedGoogle Scholar
  38. Detopoulou P, Panagiotakos DB, Antonopoulou S, Pitsavos C, Stefanadis C (2008) Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr 87:424–430PubMedGoogle Scholar
  39. Drachman DA, Glosser G, Fleming P, Longenecker G (1982) Memory decline in the aged: treatment with lecithin and physostigmine. Neurology 32:944–950PubMedGoogle Scholar
  40. Figueiredo JC, Grau MV, Haile RW et al (2009) Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst 101:432–435PubMedCrossRefGoogle Scholar
  41. Fisher MC, Zeisel SH, Mar MH, Sadler TW (2002) Perturbations in choline metabolism cause neural tube defects in mouse embryos in vitro. Faseb J 16:619–621PubMedGoogle Scholar
  42. Fischer LM, Scearce JA, Mar MH et al (2005) Ad libitum choline intake in healthy individuals meets or exceeds the proposed adequate intake level. J Nutr 135:826–829PubMedGoogle Scholar
  43. Fischer LM, Dacosta KA, Kwock L et al (2007) Sex and menopausal status influence human dietary requirements for the nutrient cholin. Am J Clin Nutr 85:1275–1285PubMedGoogle Scholar
  44. Fitten LJ, Perryman KM, Gross PL, Fine H, Cummins J, Marshall C (1990) Treatment of Alzheimer’s disease with short-and long-term oral THA and lecithin: a double-blind study. Am J Psychiatry 147:239–242PubMedGoogle Scholar
  45. Fredriksen A, Meyer K, Ueland PM, Vollset SE, Grotmol T, Schneede J (2007) Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism. Hum Mutat 28:856–865PubMedCrossRefGoogle Scholar
  46. Garner SC, Mar MH, Zeisel SH (1995) Choline distribution and metabolism in pregnant rats and fetuses are influenced by the choline content of the maternal diet. J Nutr 125:2851–2858PubMedGoogle Scholar
  47. Giusti B, Saracini C, Bolli P et al (2008) Genetic analysis of 56 polymorphisms in 17 genes involved in methionine metabolism in patients with abdominal aortic aneurysm. J Med Genet 45:721–730PubMedCrossRefGoogle Scholar
  48. Glunde K, Serkova NJ (2006) Therapeutic targets and biomarkers identified in cancer choline phospholipid metabolism. Pharmacogenomics 7:1109–1123PubMedCrossRefGoogle Scholar
  49. Harris CM, Dysken MW, Fovall P, Davis JM (1983) Effect of lecithin on memory in normal adults. Am J Psychiatry 140:1010–1012PubMedGoogle Scholar
  50. Haussinger D (2004) Neural control of hepatic osmolytes and parenchymal cell hydration. Anat Rec A Discov Mol Cell Evol Biol 280:893–900PubMedCrossRefGoogle Scholar
  51. Hazra A, Wu K, Kraft P, Fuchs CS, Giovannucci EL, Hunter DJ (2007) Twenty-four non-synonymous polymorphisms in the one-carbon metabolic pathway and risk of colorectal adenoma in the Nurses’ Health Study. Carcinogenesis 28:1510–1519PubMedCrossRefGoogle Scholar
  52. Heil SG, Lievers KJ, Boers GH et al (2000) Betaine-homocysteine methyltransferase (BHMT): genomic sequencing and relevance to hyperhomocysteinemia and vascular disease in humans. Mol Genet Metab 71:511–519PubMedCrossRefGoogle Scholar
  53. Holm PI, Bleie O, Ueland PM et al (2004) Betaine as a determinant of postmethionine load total plasma homocysteine before and after B-vitamin supplementation. Arterioscler Thromb Vasc Biol 24:301–307PubMedCrossRefGoogle Scholar
  54. Holm PI, Hustad S, Ueland PM, Vollset SE, Grotmol T, Schneede J (2007) Modulation of the homocysteine-betaine relationship by methylenetetrahydrofolate reductase 677 C->T genotypes and B-vitamin status in a large-scale epidemiological study. J Clin Endocrinol Metab 92:1535–1541PubMedCrossRefGoogle Scholar
  55. Holm PI, Ueland PM, Vollset SE et al (2005) Betaine and folate status as cooperative determinants of plasma homocysteine in humans. Arterioscler Thromb Vasc Biol 25:379–385PubMedCrossRefGoogle Scholar
  56. Huang P, Frohman MA (2007) The potential for phospholipase D as a new therapeutic target. Expert Opin Ther Targets 11:707–716PubMedCrossRefGoogle Scholar
  57. Hustad S, Midttun O, Schneede J, Vollset SE, Grotmol T, Ueland PM (2007) The methylenetetrahydrofolate reductase 677C–>T polymorphism as a modulator of a B vitamin network with major effects on homocysteine metabolism. Am J Hum Genet 80:846–855PubMedCrossRefGoogle Scholar
  58. Janardhan S, Srivani P, Sastry GN (2006) Choline kinase: an important target for cancer. Curr Med Chem 13:1169–1186PubMedCrossRefGoogle Scholar
  59. Johansson M, Van Guelpen B, Vollset SE et al (2009) One-carbon metabolism and prostate cancer risk: prospective investigation of seven circulating B vitamins and metabolites. Cancer Epidemiol Biomarkers Prev 18:1538–1543PubMedCrossRefGoogle Scholar
  60. Kempson SA, Montrose MH (2004) Osmotic regulation of renal betaine transport: transcription and beyond. Pflugers Arch 449:227–234PubMedGoogle Scholar
  61. Kettunen H, Tiihonen K, Peuranen S, Saarinen MT, Remus JC (2001) Dietary betaine accumulates in the liver and intestinal tissue and stabilizes the intestinal epithelial structure in healthy and coccidia-infected broiler chicks. Comp Biochem Physiol A Mol Integr Physiol 130:759–769PubMedCrossRefGoogle Scholar
  62. Kharbanda KK, Mailliard ME, Baldwin CR, Beckenhauer HC, Sorrell MF, Tuma DJ (2007) Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway. J Hepatol 46:314–321PubMedCrossRefGoogle Scholar
  63. Kharbanda KK, Todero SL, Ward BW, Cannella JJ 3rd, Tuma DJ (2009) Betaine administration corrects ethanol-induced defective VLDL secretion. Mol Cell Biochem 327:75–78PubMedCrossRefGoogle Scholar
  64. Kim YI (2008) Folic acid supplementation and cancer risk: point. Cancer Epidemiol Biomarkers Prev 17:2220–2225PubMedCrossRefGoogle Scholar
  65. Kim YI, Miller JW, Dacosta KA et al (1994) Severe folate deficiency causes secondary depletion of choline and phosphocholine in rat liver. J Nutr 124:2197–2203PubMedGoogle Scholar
  66. Kohlmeier M, daCosta KA, Fischer LM, Zeisel SH (2005) Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans. Proc Nat Acad Sci Usa 102:16025–16030PubMedCrossRefGoogle Scholar
  67. Konstantinova SV, Tell GS, Vollset SE, Nygard O, Bleie O, Ueland PM (2008a) Divergent associations of plasma choline and betaine with components of metabolic syndrome in middle age and elderly men and women. J Nutr 138:914–920PubMedGoogle Scholar
  68. Konstantinova SV, Tell GS, Vollset SE, Ulvik A, Drevon CA, Ueland PM (2008b) Dietary patterns, food groups, and nutrients as predictors of plasma choline and betaine in middle-aged and elderly men and women. Am J Clin Nutr 88:1663–1669PubMedCrossRefGoogle Scholar
  69. Kotronen A, Yki-Jarvinen H (2008) Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 28:27–38PubMedCrossRefGoogle Scholar
  70. Koushik A, Kraft P, Fuchs CS et al (2006) Nonsynonymous polymorphisms in genes in the one-carbon metabolism pathway and associations with colorectal cancer. Cancer Epidemiol Biomarkers Prev 15:2408–2417PubMedCrossRefGoogle Scholar
  71. Kovacheva VP, Davison JM, Mellott TJ et al (2009) Raising gestational choline intake alters gene expression in DMBA-evoked mammary tumors and prolongs survival. Faseb J 23:1054–1063PubMedCrossRefGoogle Scholar
  72. Ladd SL, Sommer SA, LaBerge S, Toscano W (1993) Effect of phosphatidylcholine on explicit memory. Clin Neuropharmacol 16:540–549PubMedCrossRefGoogle Scholar
  73. Lang F (2007) Mechanisms and significance of cell volume regulation. J Am Coll Nutr 26:613S–623SPubMedGoogle Scholar
  74. LeLeiko RM, Vaccari CS, Sola S et al (2009) Usefulness of elevations in serum choline and free F2)-isoprostane to predict 30-day cardiovascular outcomes in patients with acute coronary syndrome. Am J Cardiol 104:638–643PubMedCrossRefGoogle Scholar
  75. Lever M, George PM, Dellow WJ, Scott RS, Chambers ST (2005) Homocysteine, glycine betaine, and N, N-dimethylglycine in patients attending a lipid clinic. Metabolism 54:1–14PubMedCrossRefGoogle Scholar
  76. Levy R (1982) Lecithin in Alzheimer’s disease. Lancet 2:671–672PubMedCrossRefGoogle Scholar
  77. Lim CH, Bot AG, de Jonge HR, Tilly BC (2007) Osmosignaling and volume regulation in intestinal epithelial cells. Methods Enzymol 428:325–342PubMedCrossRefGoogle Scholar
  78. Lin CS, Wu RD (1986) Choline oxidation and choline dehydrogenase. J Protein Chem 5:193–200CrossRefGoogle Scholar
  79. Little A, Levy R, Chuaqui-Kidd P, Hand D (1985) A double-blind, placebo controlled trial of high-dose lecithin in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 48:736–742PubMedCrossRefGoogle Scholar
  80. Lockman PR, Allen DD (2002) The transport of choline. Drug Dev Ind Pharm 28:749–771PubMedCrossRefGoogle Scholar
  81. Lv S, Fan R, Du Y et al (2009) Betaine supplementation attenuates atherosclerotic lesion in apolipoprotein E-deficient mice. Eur J Nutr 48:205–212PubMedCrossRefGoogle Scholar
  82. McCann JC, Hudes M, Ames BN (2006) An overview of evidence for a causal relationship between dietary availability of choline during development and cognitive function in offspring. Neurosci Biobehav Rev 30:696–712PubMedCrossRefGoogle Scholar
  83. McGregor DO, Dellow WJ, Lever M, George PM, Robson RA, Chambers ST (2001) Dimethylglycine accumulates in uremia and predicts elevated plasma homocysteine concentrations. Kidney Int 59:2267–2272PubMedGoogle Scholar
  84. McGregor DO, Dellow WJ, Robson RA, Lever M, George PM, Chambers ST (2002) Betaine supplementation decreases post-methionine hyperhomocysteinernia in chronic renal failure. Kidney Int 61:1040–1046PubMedCrossRefGoogle Scholar
  85. McMahon KE, Farrell PM (1985) Measurement of free choline concentrations in maternal and neonatal blood by micropyrolysis gas chromatography. Clin Chim Acta 149:1–12PubMedCrossRefGoogle Scholar
  86. Miglio F, Rovati LC, Santoro A, Setnikar I (2000) Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study. Arzneimittelforschung 50:722–727PubMedGoogle Scholar
  87. Moat SJ, Madhavan A, Taylor SY et al (2006) High-but not low-dose folic acid improves endothelial function in coronary artery disease. Eur J Clin Invest 36:850–859PubMedCrossRefGoogle Scholar
  88. Mockel M, Danne O, Muller R et al (2008) Development of an optimized multimarker strategy for early risk assessment of patients with acute coronary syndromes. Clin Chim Acta 393:103–109PubMedCrossRefGoogle Scholar
  89. Mohs RC, Davis KL (1980) Choline chloride effects on memory: correlation with the effects of physostigmine. Psychiatry Res 2:149–156PubMedCrossRefGoogle Scholar
  90. Molloy AM, Mills JL, Cox C et al (2005) Choline and homocysteine interrelations in umbilical cord and maternal plasma at delivery. Am J Clin Nutr 82:836–842PubMedGoogle Scholar
  91. Morin I, Platt R, Weisberg I et al (2003) Common variant in betaine-homocysteine methyltransferase (BHMT) and risk for spina bifida. Am J Med Genet 119A:172–176PubMedCrossRefGoogle Scholar
  92. Morse DL, Carroll D, Day S et al (2009) Characterization of breast cancers and therapy response by MRS and quantitative gene expression profiling in the choline pathway. NMR Biomed 22:114–127PubMedCrossRefGoogle Scholar
  93. Neuhofer W, Beck FX (2005) Cell survival in the hostile environment of the renal medulla. Annu Rev Physiol 67:531–555PubMedCrossRefGoogle Scholar
  94. Niculescu MD, Craciunescu CN, Zeisel SH (2006) Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains. Faseb J 20:43–49PubMedCrossRefGoogle Scholar
  95. Nitsch RM, Blusztajn JK, Pittas AG, Slack BE, Growdon JH, Wurtman RJ (1992) Evidence for a membrane defect in Alzheimer disease brain. Proc Natl Acad Sci USA 89:1671–1675PubMedCrossRefGoogle Scholar
  96. O’Donoghue N, Sweeney T, Donagh R, Clarke KJ, Porter RK (2009) Control of choline oxidation in rat kidney mitochondria. Biochim Biophys Acta 1787:1135–1139PubMedCrossRefGoogle Scholar
  97. Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J (1998) Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr 157(Suppl 2):S77–S83PubMedCrossRefGoogle Scholar
  98. Olsen M, Sarup A, Larsson OM, Schousboe A (2005) Effect of hyperosmotic conditions on the expression of the betaine-GABA-transporter (BGT-1) in cultured mouse astrocytes. Neurochem Res 30:855–865PubMedCrossRefGoogle Scholar
  99. Olthof MR, Verhoef P (2005) Effects of betaine intake on plasma homocysteine concentrations and consequences for health. Curr Drug Metab 6:15–22PubMedCrossRefGoogle Scholar
  100. Olthof MR, vanVliet T, Boelsma E, Verhoef P (2003) Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. J Nutr 133:4135–4138PubMedGoogle Scholar
  101. Olthof MR, Brink EJ, Katan MB, Verhoef P (2005a) Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. Am J Clin Nutr 82:111–117PubMedGoogle Scholar
  102. Olthof MR, van Vliet T, Verhoef P, Zock PL, Katan MB (2005b) Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans. PLoS Med 2:446–456CrossRefGoogle Scholar
  103. Olthof MR, Bots ML, Katan MB, Verhoef P (2006) Acute effect of folic acid, betaine, and serine supplements on flow-mediated dilation after methionine loading: a randomized trial. PLoS Clin Trials 1(1):e4Google Scholar
  104. Ozarda Ilcol Y, Uncu G, Ulus IH (2002) Free and phospholipid-bound choline concentrations in serum during pregnancy, after delivery and in newborns. Arch Physiol Biochem 110:393–399PubMedCrossRefGoogle Scholar
  105. Park EI, Garrow TA (1999) Interaction between dietary methionine and methyl donor intake on rat liver betaine-homocysteine methyltransferase gene expression and organization of the human gene. J Biol Chem 274:7816–7824PubMedCrossRefGoogle Scholar
  106. Petronini PG, Alfieri RR, Losio MN et al (2000) Induction of BGT-1 and amino acid system A transport activities in endothelial cells exposed to hyperosmolarity. Am J Physiol Regul Integr Comp Physiol 279:R1580–R1589PubMedGoogle Scholar
  107. Purohit V, Abdelmalek MF, Barve S et al (2007) Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium. Am J Clin Nutr 86:14–24PubMedGoogle Scholar
  108. Resseguie M, Song JN, Niculescu MD, daCosta KA, Randall TA, Zeisel SH (2007) Phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes. Faseb J 21:2622–2632PubMedCrossRefGoogle Scholar
  109. Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610PubMedCrossRefGoogle Scholar
  110. Sakamoto A, Nishimura Y, Ono H, Sakura N (2002) Betaine and homocysteine concentrations in foods. Pediatr Int 44:409–413PubMedCrossRefGoogle Scholar
  111. Saver JL (2008) Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair. Rev Neurol Dis 5:167–177PubMedGoogle Scholar
  112. Schafer C, Hoffmann L, Heldt K et al (2007) Osmotic regulation of betaine homocysteine-S-methyltransferase expression in H4IIE rat hepatoma cells. Am J Physiol Gastrointest Liver Physiol 292:G1089–G1098PubMedCrossRefGoogle Scholar
  113. Schliess F, Haussinger D (2002) The cellular hydration state: a critical determinant for cell death and survival. Biol Chem 383:577–583PubMedCrossRefGoogle Scholar
  114. Schwab U, Törrönen A, Toppinen L et al (2002) Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. Am J Clin Nutr 76:961–967PubMedGoogle Scholar
  115. Schwahn BC, Laryea MD, Chen ZT et al (2004) Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency. Biochem J 382:831–840PubMedCrossRefGoogle Scholar
  116. Shaw GM, Carmichael SL, Yang W, Selvin S, Schaffer DM (2004) Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. Am J Epidemiol 160:102–109PubMedCrossRefGoogle Scholar
  117. Shaw GM, Finnell RH, Blom HJ et al (2009) A prospective case-control study of choline and risks of neural tube defect-affected pregnancies in a folate fortified population. Epidemiology 20:714–719PubMedCrossRefGoogle Scholar
  118. Signore C, Ueland PM, Troendle J, Mills JL (2008) Choline concentrations in human maternal and cord blood and intelligence at 5 y of age. Am J Clin Nutr 87:896–902PubMedGoogle Scholar
  119. Sitaram N, Weingartner H, Caine ED, Gillin JC (1978) Choline: selective enhancement of serial learning and encoding of low imagery words in man. Life Sci 22:1555–1560PubMedCrossRefGoogle Scholar
  120. Slow S, Donaggio M, Cressey P, Lever M, George P, Chambers S (2005) The betaine content of New Zealand foods and estimated intake in the New Zealand diet. J Food Composit Anal 18:473–485CrossRefGoogle Scholar
  121. Slow S, Lever M, Chambers ST, George PM (2009) Plasma dependent and independent accumulation of betaine in male and female rat tissues. Physiol Res 58:403–410PubMedGoogle Scholar
  122. Song JN, daCosta KA, Fischer LM et al (2005) Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). Faseb J 19:1266–1271PubMedCrossRefGoogle Scholar
  123. Spiers PA, Myers D, Hochanadel GS, Lieberman HR, Wurtman RJ (1996) Citicoline improves verbal memory in aging. Arch Neurol 53:441–448PubMedGoogle Scholar
  124. Stead LM, Brosnan JT, Brosnan ME, Vance DE, Jacobs RL (2006) Is it time to reevaluate methyl balance in humans? Am J Clin Nutr 83:5–10PubMedGoogle Scholar
  125. Sweiry JH, Yudilevich DL (1985) Characterization of choline transport at maternal and fetal interfaces of the perfused guinea-pig placenta. J Physiol 366:251–266PubMedGoogle Scholar
  126. Thomas JD, Abou EJ, Dominguez HD (2009) Prenatal choline supplementation mitigates the adverse effects of prenatal alcohol exposure on development in rats. Neurotoxicol Teratol 31:303–311PubMedCrossRefGoogle Scholar
  127. Troen AM, Chao WH, Crivello NA et al (2008) Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by dietary methionine without lowering plasma homocysteine. J Nutr 138:2502–2509PubMedCrossRefGoogle Scholar
  128. Ueland PM, Holm PI, Hustad S (2005) Betaine: a key modulator of one-carbon metabolism and homocysteine status. Clin Chem Lab Med 43:1069–1075PubMedCrossRefGoogle Scholar
  129. Vance DE (2008) Role of phosphatidylcholine biosynthesis in the regulation of lipoprotein homeostasis. Curr Opin Lipidol 19:229–234PubMedCrossRefGoogle Scholar
  130. Vance DE, Li Z, Jacobs RL (2007) Hepatic phosphatidylethanolamine N-methyltransferase, unexpected roles in animal biochemistry and physiology. J Biol Chem 282:33237–33241PubMedCrossRefGoogle Scholar
  131. VarelaMoreiras G, Selhub J, Da Costa KA, Zeisel SH (1992) Effect of chronic choline deficiency in rats on liver folate content and distribution. J Nutr Biochem 3:519–522CrossRefGoogle Scholar
  132. VelzingAarts FV, Holm PI, Fokkema MR, vanderDijs FP, Ueland PM, Muskiet FA (2005) Plasma choline and betaine and their relation to plasma homocysteine in normal pregnancy. Am J Clin Nutr 81:1383–1389Google Scholar
  133. Venkatesu P, Lee MJ, Lin HM (2009) Osmolyte counteracts urea-induced denaturation of alpha-chymotrypsin. J Phys Chem B 113:5327–5338PubMedCrossRefGoogle Scholar
  134. Wallace JMW, Bonham MP, Strain JJ et al (2008) Homocysteine concentration, related B vitamins, and betaine in pregnant women recruited to the Seychelles Child Development Study. Am J Clin Nutr 87:391–397PubMedGoogle Scholar
  135. Warskulat U, Reinen A, Grether-Beck S, Krutmann J, Haussinger D (2004) The osmolyte strategy of normal human keratinocytes in maintaining cell homeostasis. J Invest Dermatol 123:516–521PubMedCrossRefGoogle Scholar
  136. Warskulat U, Brookmann S, Felsner I, Brenden H, Grether-Beck S, Haussinger D (2008) Ultraviolet A induces transport of compatible organic osmolytes in human dermal fibroblasts. Exp Dermatol 17:1031–1036PubMedCrossRefGoogle Scholar
  137. Waterland RA, Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23:5293–5300PubMedCrossRefGoogle Scholar
  138. Waterland RA, Dolinoy DC, Lin JR, Smith CA, Shi X, Tahiliani KG (2006) Maternal methyl supplements increase offspring DNA methylation at Axin Fused. Genesis 44:401–406PubMedCrossRefGoogle Scholar
  139. Weik C, Warskulat U, Bode J, Peters-Regehr T, Haussinger D (1998) Compatible organic osmolytes in rat liver sinusoidal endothelial cells. Hepatology 27:569–575PubMedCrossRefGoogle Scholar
  140. Weinstein HC, Teunisse S, van Gool WA (1991) Tetrahydroaminoacridine and lecithin in the treatment of Alzheimer’s disease. Effect on cognition, functioning in daily life, behavioural disturbances and burden experienced by the carers. J Neurol 238:34–38PubMedCrossRefGoogle Scholar
  141. Weisberg IS, Park E, Ballman KV et al (2003) Investigations of a common genetic methyltransferase (BHMT) variant in betaine-homocysteine in coronary artery disease. Atherosclerosis 167:205–214PubMedCrossRefGoogle Scholar
  142. Wurtman RJ, Cansev M, Sakamoto T, Ulus IH (2009) Use of phosphatide precursors to promote synaptogenesis. Annu Rev Nutr 29:59–87PubMedCrossRefGoogle Scholar
  143. Xu X, Gammon MD, Wetmur JG et al (2008a) B-vitamin intake, one-carbon metabolism, and survival in a population-based study of women with breast cancer. Cancer Epidemiol Biomarkers Prev 17:2109–2116PubMedCrossRefGoogle Scholar
  144. Xu XR, Gammon MD, Zeisel SH et al (2008b) Choline metabolism and risk of breast cancer in a population-based study. Faseb J 22:2045–2052PubMedCrossRefGoogle Scholar
  145. Yamauchi A, Uchida S, Kwon HM et al (1992) Cloning of a Na(+)- and Cl(-)-dependent betaine transporter that is regulated by hypertonicity. J Biol Chem 267:649–652PubMedGoogle Scholar
  146. Yap S (2003) Classical homocystinuria: vascular risk and its prevention. J Inherit Metab Dis 26:259–265PubMedCrossRefGoogle Scholar
  147. Yates AA, Schlicker SA, Suitor CW (1998) Dietary Reference Intakes: the new basis for recommendations for calcium and related nutrients, B vitamins, and choline. J Am Diet Assoc 98:699–706PubMedCrossRefGoogle Scholar
  148. Zeisel SH (1991) Choline, an essential nutrient for humans. Faseb J 5:2093–2098PubMedGoogle Scholar
  149. Zeisel SH (2000) Choline: an essential nutrient for humans. Nutrition 16:669–671PubMedCrossRefGoogle Scholar
  150. Zeisel SH (2006a) Betaine supplementation and blood lipids: fact or artifact? Nutr Rev 64:77–79PubMedCrossRefGoogle Scholar
  151. Zeisel SH (2006b) Choline: critical role during fetal development and dietary requirements in adults. Annu Rev Nutr 26:229–250PubMedCrossRefGoogle Scholar
  152. Zeisel SH (2006c) The fetal origins of memory: the role of dietary choline in optimal brain development. J Pediatr 149:S131–S136PubMedCrossRefGoogle Scholar
  153. Zeisel SH (2007) Gene response elements, genetic polymorphisms and epigenetics influence the human dietary requirement for choline. Iubmb Life 59:380–387PubMedCrossRefGoogle Scholar
  154. Zeisel SH (2009a) Epigenetic mechanisms for nutrition determinants of later health outcomes. Am J Clin Nutr 89:1488S–1493SPubMedCrossRefGoogle Scholar
  155. Zeisel SH (2009b) Importance of methyl donors during reproduction. Am J Clin Nutr 89:673S–677SPubMedCrossRefGoogle Scholar
  156. Zeisel SH, Blusztajn JK (1994) Choline and human nutrition. Annu Rev Nutr 14:269–296PubMedCrossRefGoogle Scholar
  157. Zeisel SH, Epstein MF, Wurtman RJ (1980) Elevated choline concentration in neonatal plasma. Life Sci 26:1827–1831PubMedCrossRefGoogle Scholar
  158. Zeisel SH, Mar MH, Howe JC, Holden JM (2003) Concentrations of choline-containing compounds and betaine in common foods. J Nutr 133:1302–1307PubMedGoogle Scholar
  159. Zeisel SH, Mar MH, Zhou Z, da Costa KA (1995) Pregnancy and lactation are associated with diminished concentrations of choline and its metabolites in rat liver. J Nutr 125:3049–3054PubMedGoogle Scholar
  160. Zhang F, Warskulat U, Wettstein M, Haussinger D (1996) Identification of betaine as an osmolyte in rat liver macrophages (Kupffer cells). Gastroenterology 110:1543–1552PubMedCrossRefGoogle Scholar
  161. Zhao Y, Su B, Jacobs RL et al (2009) Lack of phosphatidylethanolamine N-methyltransferase alters plasma VLDL phospholipids and attenuates atherosclerosis in mice. Arterioscler Thromb Vasc Biol 29:1349–1355PubMedCrossRefGoogle Scholar
  162. Zhu HP, Curry S, Wen S et al (2005) Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts? Am J Med Genet Part A 135A:274–277CrossRefGoogle Scholar
  163. Zhu XN, Song JN, Mar MH, Edwards LJ, Zeisel SH (2003) Phosphatidylethanolamine N-methyltransferase (PEMT) knockout mice have hepatic steatosis and abnormal hepatic choline metabolite concentrations despite ingesting a recommended dietary intake of choline. Biochem J 370:987–993PubMedCrossRefGoogle Scholar

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© SSIEM and Springer 2010

Authors and Affiliations

  1. 1.Section for Pharmacology, Institute of MedicineUniversity of BergenBergenNorway
  2. 2.Laboratory of Clinical BiochemistryHaukeland University HospitalBergenNorway

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