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Licensed Unlicensed Requires Authentication Published by De Gruyter September 21, 2011

Betaine: a key modulator of one-carbon metabolism and homocysteine status

  • Per Magne Ueland , Pål I. Holm and Steinar Hustad

Abstract

Betaine serves as a methyl donor in a reaction converting homocysteine to methionine, catalysed by the enzyme betaine-homocysteine methyltransferase. It has been used for years to lower the concentration of plasma total homocysteine (tHcy) in patients with homocystinuria, and has recently been shown to reduce fasting and in particular post-methionine load (PML) tHcy in healthy subjects.

Betaine exists in plasma at concentrations of about 30μmol/L; it varies 10-fold (from 9 to 90μmol/L) between individuals, but the intra-individual variability is small. Major determinants are choline, dimethylglycine and folate in plasma, folic acid intake and gender.

Recent studies have demonstrated that plasma betaine is a stronger determinant of PML tHcy than are vitamin B6 and folate. The betaine-PML tHcy relationship is attenuated after supplementation with B-vitamins, and is most pronounced in subjects with low folate. Betaine shows a weaker association with fasting tHcy (than with PML tHcy), and also this association is most pronounced in subjects with low folate. In pregnancy, plasma betaine declines until gestational week 20, and thereafter remains constant. From gestational week 20 onwards, fasting tHcy shows a strong inverse association with plasma betaine, and betaine becomes a stronger predictor than folate of fasting tHcy.

To conclude, betaine status is a component of an individual's biochemical make-up with ramifications to one-carbon metabolism. Betaine status should be investigated in pathologies related to altered metabolism of homocysteine and folate, including cardiovascular disease, cancer and neural tube defects.


Corresponding author: Dr. Per Magne Ueland, LOCUS for Homocysteine and Related Vitamins, Armauer Hansens hus, University of Bergen, 5021 Bergen, Norway Phone: +47-5597-3147, Fax: +47-5597-4605,

References

1. Yancey PH, Clark ME, Hand SC, Bowlus RD, Somero GN. Living with water stress: evolution of osmolyte systems. Science 1982; 217:1214–22.10.1126/science.7112124Search in Google Scholar

2. Lang F, Busch GL, Volkl H. The diversity of volume regulatory mechanisms. Cell Physiol Biochem 1998; 8:1–45.10.1159/000016269Search in Google Scholar

3. Craig SA. Betaine in human nutrition. Am J Clin Nutr 2004; 80:539–49.10.1093/ajcn/80.3.539Search in Google Scholar

4. Sakamoto A, Nishimura Y, Ono H, Sakura N. Betaine and homocysteine concentrations in foods. Pediatr Int 2002; 44:409–13.10.1046/j.1442-200X.2002.01591.xSearch in Google Scholar

5. Zeisel SH, Mar MH, Howe JC, Holden JM. Concentrations of choline-containing compounds and betaine in common foods. J Nutr 2003; 133:1302–7.10.1093/jn/133.5.1302Search in Google Scholar

6. Slow S, Donaggio M, Cressey PJ, Lever M, George PM, Chambers ST. The betaine content of New Zealand foods and estimated intake in the New Zealand diet. J Food Comp Anal 2005; 18:473–85.10.1016/j.jfca.2004.05.004Search in Google Scholar

7. Schwahn BC, Hafner D, Hohlfeld T, Balkenhol N, Laryea MD, Wendel U. Pharmacokinetics of oral betaine in healthy subjects and patients with homocystinuria. Br J Clin Pharmacol 2003; 55:6–13.10.1046/j.1365-2125.2003.01717.xSearch in Google Scholar

8. Rhodes D, Hanson AD. Quaternary ammonium and tertiary sulfonium compounds in higher plants. Rev Plant Physiol Mol Biol 1993; 44:357–84.10.1146/annurev.pp.44.060193.002041Search in Google Scholar

9. Kempson SA, Montrose MH. Osmotic regulation of renal betaine transport: transcription and beyond. Pflugers Arch 2004; 449:227–34.Search in Google Scholar

10. Zeisel SH, Blusztajn JK. Choline and human nutrition. Annu Rev Nutr 1994; 14:269–96.10.1146/annurev.nu.14.070194.001413Search in Google Scholar

11. Zeisel SH. Choline: an essential nutrient for humans. Nutrition 2000; 16:669–71.10.1016/S0899-9007(00)00349-XSearch in Google Scholar

12. Uchida T, Yamashita S. Molecular cloning, characterization, and expression in Escherichia coli of a cDNA encoding mammalian choline kinase. J Biol Chem 1992; 267:10156–62.10.1016/S0021-9258(19)50213-7Search in Google Scholar

13. Porter RK, Scott JM, Brand MD. Choline transport into rat liver mitochondria. Characterization and kinetics of a specific transporter. J Biol Chem 1992; 267:14637–46.10.1016/S0021-9258(18)42089-3Search in Google Scholar

14. Park EI, Garrow TA. 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 1999; 274:7816–24.10.1074/jbc.274.12.7816Search in Google Scholar

15. Schliess F, Haussinger D. The cellular hydration state: a critical determinant for cell death and survival. Biol Chem 2002; 383:577–83.10.1515/BC.2002.059Search in Google Scholar

16. Alfieri RR, Cavazzoni A, Petronini PG, Bonelli MA, Caccamo AE, Borghetti AF, et al. Compatible osmolytes modulate the response of porcine endothelial cells to hypertonicity and protect them from apoptosis. J Physiol 2002; 540:499–508.10.1113/jphysiol.2001.013395Search in Google Scholar

17. Delgado-Reyes CV, Garrow TA. High sodium chloride intake decreases betaine-homocysteine S-methyltransferase expression in guinea pig liver and kidney. Am J Physiol Regul Integr Comp Physiol 2005; 288:R182–7.10.1152/ajpregu.00406.2004Search in Google Scholar

18. Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem 1990; 1:228–37.10.1016/0955-2863(90)90070-2Search in Google Scholar

19. Finkelstein JD, Martin JJ. Methionine metabolism in mammals. Distribution of homocysteine between competing pathways. J Biol Chem 1984; 259:9508–13.10.1016/S0021-9258(17)42728-1Search in Google Scholar

20. Schwahn BC, Chen Z, Laryea MD, Wendel U, Lussier-Cacan S, Genest J Jr, et al. Homocysteine-betaine interactions in a murine model of 5,10-methylenetetrahydrofolate reductase deficiency. FASEB J 2003; 17:512–4.10.1096/fj.02-0456fjeSearch in Google Scholar PubMed

21. Schwahn BC, Laryea MD, Chen Z, Melnyk S, Pogribny I, Garrow T, et al. Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency. Biochem J 2004; 382:831–40.10.1042/BJ20030822Search in Google Scholar

22. Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr 2002; 132:2333S–5S.10.1093/jn/132.8.2333SSearch in Google Scholar

23. Selhub J, Miller JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr 1992; 55:131–8.10.1093/ajcn/55.1.131Search in Google Scholar

24. Reed MC, Nijhout HF, Sparks R, Ulrich CM. A mathematical model of the methionine cycle. J Theor Biol 2004; 226:33–43.10.1016/j.jtbi.2003.08.001Search in Google Scholar

25. Allen RH, Stabler SP, Lindenbaum J. Serum betaine, N,N-dimethylglycine and N-methylglycine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism. Metabolism 1993; 42:1448–60.10.1016/0026-0495(93)90198-WSearch in Google Scholar

26. Lever M, Sizeland PC, Bason LM, Hayman CM, Chambers ST. Glycine betaine and proline betaine in human blood and urine. Biochim Biophys Acta 1994; 1200:259–64.10.1016/0304-4165(94)90165-1Search in Google Scholar

27. Lever M, Sizeland PC, Bason LM, Hayman CM, Robson RA, Chambers ST. Abnormal glycine betaine content of the blood and urine of diabetic and renal patients. Clin Chim Acta 1994; 230:69–79.10.1016/0009-8981(94)90090-6Search in Google Scholar

28. Holm PI, Ueland PM, Kvalheim G, Lien EA. Determination of choline, betaine, and dimethylglycine in plasma by a high-throughput method based on normal-phase chromatography-tandem mass spectrometry. Clin Chem 2003; 49:286–94.10.1373/49.2.286Search in Google Scholar

29. Holm PI, Bleie O, Ueland PM, Lien EA, Refsum H, Nordrehaug JE, et al. Betaine as a determinant of postmethionine load total plasma homocysteine before and after B-vitamin supplementation. Arterioscler Thromb Vasc Biol 2004; 24:301–7.10.1161/01.ATV.0000114569.54976.31Search in Google Scholar

30. Velzing-Aarts FV, Holm PI, Fokkema MR, van der Dijs FP, Ueland PM, Muskiet FA. Plasma choline, betaine and their relation to plasma homocysteine in normal pregnancy. Am J Clin Nutr 2005; 81:1383–9.10.1093/ajcn/81.6.1383Search in Google Scholar

31. Finkelstein JD, Kyle WE, Harris BJ. Methionine metabolism in mammals. Regulation of homocysteine methyltransferases in rat tissue. Arch Biochem Biophys 1971; 146:84–92.10.1016/S0003-9861(71)80044-9Search in Google Scholar

32. Lever M, Sizeland PC, Frampton CM, Chambers ST. Short and long-term variation of plasma glycine betaine concentrations in humans. Clin Biochem 2004; 37:184–90.10.1016/j.clinbiochem.2003.11.004Search in Google Scholar

33. Lever M, George PM, Dellow WJ, Scott RS, Chambers ST. Homocysteine, glycine betaine, and N,N-dimethylglycine in patients attending a lipid clinic. Metabolism 2005; 54:1–14.10.1016/j.metabol.2004.07.007Search in Google Scholar

34. Melse-Boonstra A, Holm PI, Ueland P, Olthof M, Clarke R, Verhoef P. Betaine concentration as a determinant of fasting total homocysteine concentrations and the effect of folic acid supplementation. Am J Clin Nutr 2005; 81:1378–82.10.1093/ajcn/81.6.1378Search in Google Scholar

35. Holm PI, Ueland PM, Vollset SE, Midttun O, Blom HJ, Keijzer MB, et al. Betaine and folate status as cooperative determinants of plasma homocysteine in humans. Arterioscler Thromb Vasc Biol 2005; 25:379–85.10.1161/01.ATV.0000151283.33976.e6Search in Google Scholar

36. Sizeland PC, Chambers ST, Lever M, Bason LM, Robson RA. Short-term response of nonurea organic osmolytes in human kidney to a water load and water deprivation. Am J Physiol 1995; 268:F227–33.10.1152/ajprenal.1995.268.2.F227Search in Google Scholar

37. McGregor DO, Dellow WJ, Lever M, George PM, Robson RA, Chambers ST. Dimethylglycine accumulates in uremia and predicts elevated plasma homocysteine concentrations. Kidney Int 2001; 59:2267–72.10.1046/j.1523-1755.2001.00743.xSearch in Google Scholar

38. Dellow WJ, Chambers ST, Lever M, Lunt H, Robson RA. Elevated glycine betaine excretion in diabetes mellitus patients is associated with proximal tubular dysfunction and hyperglycemia. Diabetes Res Clin Pract 1999; 43:91–9.10.1016/S0168-8227(98)00115-6Search in Google Scholar

39. Dellow WJ, Chambers ST, Barrell GK, Lever M, Robson RA. Glycine betaine excretion is not directly linked to plasma glucose concentrations in hyperglycaemia. Diabetes Res Clin Pract 2001; 52:165–9.10.1016/S0168-8227(01)00237-6Search in Google Scholar

40. Yap S. Classical homocystinuria: vascular risk and its prevention. J Inherit Metab Dis 2003; 26:259–65.10.1023/A:1024497419821Search in Google Scholar

41. Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J. Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr 1998; 157(Suppl 2):S77–83.10.1007/PL00014307Search in Google Scholar PubMed

42. Olthof MR, Verhoef P. Effects of betaine intake on plasma homocysteine concentrations and consequences for health. Curr Drug Metab 2005; 6:15–22.10.2174/1389200052997366Search in Google Scholar PubMed

43. Steenge GR, Verhoef P, Katan MB. Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr 2003; 133:1291–5.10.1093/jn/133.5.1291Search in Google Scholar PubMed

44. Olthof MR, van Vliet T, Boelsma E, Verhoef P. Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. J Nutr 2003; 133:4135–8.10.1093/jn/133.12.4135Search in Google Scholar PubMed

45. Yagisawa M, Okawa N, Shigematsu N, Nakata R. Effects of intravenous betaine on methionine-loading-induced plasma homocysteine elevation in rats. J Nutr Biochem 2004; 15:666–71.10.1016/j.jnutbio.2004.05.004Search in Google Scholar PubMed

46. Schwab U, Torronen A, Toppinen L, Alfthan G, Saarinen M, Aro A, et al. 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 2002; 76:961–7.10.1093/ajcn/76.5.961Search in Google Scholar PubMed

47. Alfthan G, Tapani K, Nissinen K, Saarela J, Aro A. The effect of low doses of betaine on plasma homocysteine in healthy volunteers. Br J Nutr 2004; 92:665–9.10.1079/BJN20041253Search in Google Scholar

48. McGregor DO, Dellow WJ, Robson RA, Lever M, George PM, Chambers ST. Betaine supplementation decreases post-methionine hyperhomocysteinemia in chronic renal failure. Kidney Int 2002; 61:1040–6.10.1046/j.1523-1755.2002.00199.xSearch in Google Scholar PubMed

49. Olthof MR, Brink EJ, Katan MB, Verhoef P. Choline supplemented as phosphatidylcholine 1 line decreases fasting and post-methionine plasma homocysteine concentrations in healthy men. Am J Clin Nutr 2005; 82:111–7.10.1093/ajcn/82.1.111Search in Google Scholar

50. da Costa KA, Gaffney CE, Fischer LM, Zeisel SH. Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load. Am J Clin Nutr 2005; 81:440–4.10.1093/ajcn.81.2.440Search in Google Scholar PubMed PubMed Central

51. Zeisel SH, Da Costa KA, Franklin PD, Alexander EA, Lamont JT, Sheard NF, et al. Choline, an essential nutrient for humans. FASEB J 1991; 5:2093–8.10.1096/fasebj.5.7.2010061Search in Google Scholar

52. Buchman AL, Dubin M, Jenden D, Moukarzel A, Roch MH, Rice K, et al. Lecithin increases plasma free choline and decreases hepatic steatosis in long-term total parenteral nutrition patients. Gastroenterology 1992; 102:1363–70.10.1016/0016-5085(92)90777-VSearch in Google Scholar

53. Sugiyama K, Mochizuki C, Muramatsu K. Comparative effects of choline chloride and phosphatidylcholine on plasma and liver lipid levels in rats fed a choline-deficient high cholesterol diet. J Nutr Sci Vitaminol (Tokyo) 1987; 33:369–76.10.3177/jnsv.33.369Search in Google Scholar PubMed

54. Mason TM. The role of factors that regulate the synthesis and secretion of very-low-density lipoprotein by hepatocytes. Crit Rev Clin Lab Sci 1998; 35:461–87.10.1080/10408369891234246Search in Google Scholar PubMed

55. Schwahn BC, Brilakis IS, Lennon RJ, Laryea MD, Berger PB, Rozen R. Betaine is a determinant in of plasma lipids in men. 4th Conference on Hyperhomocysteinemia, Apr 14–16, 2005. Clin Chem Lab Med 2005; 43:A31.Search in Google Scholar

56. Refsum H, Smith AD, Ueland PM, Nexo E, Clarke R, McPartlin J, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004; 50:3–32.10.1373/clinchem.2003.021634Search in Google Scholar PubMed

57. Molloy AM, Mills BJ, Cox C, Daly SF, Conley M, Brody LC, et al. Choline and homocysteine inter-relationships in neonate and maternal plasma at delivery. Am J Clin Nutr 2005; in press.10.1093/ajcn/82.4.836Search in Google Scholar PubMed

58. Holm PI, Hustad S, Schneede J, Vollset SE, Hoff G, Ueland PM. Betaine as determinant of fasting plasma homocysteine: effect is modified by folate status and the MTHFR 677C-> T genotype [abstract]. 5th International Conference on Homocysteine Metabolism, Milano, June 26–30, 2005.Search in Google Scholar

59. Suh JR, Herbig AK, Stover PJ. New perspectives on folate catabolism. Annu Rev Nutr 2001; 21:255–82.10.1146/annurev.nutr.21.1.255Search in Google Scholar PubMed

Published Online: 2011-9-21
Published in Print: 2005-10-1

©2005 by Walter de Gruyter Berlin New York

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