Browse > Article

Genomic DNA Methylation Status and Plasma Homocysteine in Choline- and Folate-Deficient Rats  

Mun, Ju-Ae (Department of Food and Nutrition, College of Bio-Nano Science, Hannam University)
Min, Hye-Sun (Department of Food and Nutrition, College of Bio-Nano Science, Hannam University)
Publication Information
Journal of Nutrition and Health / v.40, no.1, 2007 , pp. 14-23 More about this Journal
Abstract
Elevated plasma homocysteine (Hcy) is a risk factor for cognitive dysfunction and Alzheimer disease, although the mechanism is still unknown. Both folate and betaine, a choline metabolite, play essential roles in the remethylation of Hcy to methionine. Choline deficiency may be associated with low folate status and high plasma Hcy. Alterations in DNA methylation also have established critical roles for methylation in development of the nervous system. This study was undertaken to assess the effect of choline and folate deficiency on Hcy metabolism and genomic DNA methylation status of the liver and brain. Groups of adult male Sprague Dawley rats were fed on a control, choline-deficient (CD), folate-deficient (FD) or choline/folate-deficient (CFD) diets for 8 weeks. FD resulted in a significantly lower hepatic folate (23%) (p<0.001) and brain folate (69%) (p<0.05) compared to the control group. However, plasma and brain folate remained unaltered by CD and hepatic folate reduced to 85% of the control by CD (p<0.05). Plasma Hcy was significantly increased by FD $(18.34{\pm}1.62{\mu}M)$ and CFD $(19.35{\pm}3.62{\mu}M)$ compared to the control $(6.29{\pm}0.60{\mu}M)$ (p<0.001), but remained unaltered by CD. FD depressed S-adenosylmethionine (SAM) by 59% (p<0.001) and elevated S-adenosylhomocysteine (SAM) by 47% in liver compared to the control group (p<0.001). In contrast, brain SAM levels remained unaltered in CD, FD and CFD rats. Genomic DNA methylation status was reduced by FD in liver (p<0.05) Genomic DNA hypomethylation was also observed in brain by CD, FD and CFD although it was not significantly different from the control group. Genomic DNA methylation status was correlated with folate stores in liver (r=-0.397, p<0.05) and brain (r = -0.390, p<0.05), respectively. In conclusion, our data demonsoated that genomic DNA methylation and SAM level were reduced by folate deficiency in liver, but not in brain, and correlated with folate concentration in the tissue. The fact that folate deficiency had differential effects on SAM, SAH and genomic DNA methylation in liver and brain suggests that the Hcy metabolism and DNA methylation are regulated in tissue-specific ways.
Keywords
choline; folate; homocyteine; S-adenosylmethionine; DNA methylation;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Fratiglioni L, Ahlbom A, Viitanen M, Winblad B. Risk factors for late-onset Alzheimer's disease a population-based, case-control study. Ann Neurol 33: 258-266, 1993   DOI   ScienceOn
2 Institute of Medicine, and National Academy of Sciences USA. Dietary Reference Intakes for Folate, Thiamin, Riboflavin, Niacin, Vitamin $B_{12}$, Panthothenic Acid, Biotin, and Choline, vol. 1. National Academy Press, Washiongton, D.C., 1998
3 Wainfan E, Dizik M, Stender M, Christman JK. Rapid appearance of hypomethylated DNA in livers of rats fed cancer-promoting, methyl-deficient diets. Cancer Res 49: 4094-4097, 1989
4 Varela-Moreiras G, Ragel C, Perez de Miguelsanz J. Choline deficiency and methotrexate treatment induces marked but reversible changes in hepatic folate concentrations, serum homocysteine and DNA methylation rates in rats. J Am Coll Nutr 14: 480-485, 1995   DOI
5 Parsons RB, Waring RH, Ramsden DB, Williams AC. In vitro effect of the cysteine metabolites homocysteic acid, homocysteine and cysteic acid upon human neuronal cell lines. Neurotoxicology 19: 599-603, 1998
6 Araki A, Sako Y. Determination of free and total homocysteine in human plasma by HPLC with fluorescence detection. J Chromatogr 422: 43-52, 1987   DOI
7 Min H, Im ES, Seo JS, Mun JA, Burri BJ. Effects of chronic ethanol ingestion and folate deficiency on the activity of 10-formyltetrahydrofolate dehydrogenase in rat liver. Alcohol Clin Exp Res 29: 2188-2193, 2005   DOI   ScienceOn
8 Kamath AF, Chauhan AK, Kisucka J, Dole VS, Loscalzo J, Handy DE, Wagner DD. Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood 107: 591-593, 2006   DOI   ScienceOn
9 Grieve A, Butcher SP, Griffiths R. Synaptosomal plasma membrane transport of excitatory sulphur amino acid transmitter candidates: kinetic characterisation and analysis of carrier specificity. J Neurosci Res 32: 60-68, 1992   DOI   ScienceOn
10 Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol 26: 301-307, 1997   DOI   ScienceOn
11 Surtees R, Bowron A, Leonard J. Cerebrospinal fluid and plasma total homocysteine and related metabolites in children with cystathionine beta-synthase deficiency: the effect of treatment. Pediatr Res 42: 577-582, 1997   DOI   ScienceOn
12 Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr 132(Suppl): 2333S-2335S, 2002
13 Dizik M, Christman JK, Wainfan E. Alterations in expression and methylation of specific genes in livers of rats fed a cancer promoting methyl-deficient diet. Carcinogenesis 12: 1307-1312, 1991   DOI   ScienceOn
14 Balaghi M, Wagner C. DNA methylation in folate deficiency: use of CpG methylase. Biochem Biophys Res Commun 193: 1184-1190, 1993   DOI   ScienceOn
15 Lu SC, Alvarez L, Huang ZZ, Chen L, An W, Corrales FJ, Avila MA, Kanel G, Mato JM. Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. Proc Natl Acad Sci USA 98: 5560-5565, 2001
16 Kruman II, Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L, Mattson MP. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 20: 6920-6926, 2000   DOI
17 Kim YI, Miller JW, da Costa KA, Nadeau M, Smith D, Selhub J, Zeisel SH, Mason JB. Severe folate deficiency causes secondary depletion of choline and phosphocholine in rat liver. J Nutr 124: 2197-2203, 1994   DOI
18 Fell D, Steele RD. The effects of vitamin A deficiency on hepatic folate metabolism in rats. Arch Biochem Biophys 240: 843-850, 1985   DOI   ScienceOn
19 Griffiths R, Grieve A, Allen S, Olverman HJ. Neuronal and glial plasma membrane carrier-mediated uptake of L-homocysteate is not selectively blocked by beta-p-chlorophenylglutamate. Neurosci Lett 147: 175-178, 1992   DOI   ScienceOn
20 Bhave MR, Wilson MJ, Poirier LA. c-H-ras and c-K-ras gene hypomethylation in the livers and hepatomas of rats fed methyldeficient, amino acid-defined diets. Carcinogenesis 9: 343-348, 1988   DOI   ScienceOn
21 Brot N, Weissbach H. The role of cobamides in methionine synthesis. Enzymatic formation of holoenzyme. J Biol Chem 241: 2024-2028, 1966
22 Tamura T. Microbiological assay of folate, in Folic Acid Metabolism in Health and Disease (Picciano MF, Stokstad ELR, Gregory JF eds.), pp.121-137. Wiley-Liss, New York, 1990
23 Scott JM. Folate-vitamin $B_{12}$ interrelationships in the central nervous system. Proc Nutr Soc 51: 219-224, 1992
24 Wainfan E, Poirier LA. Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. Cancer Res 52 (Suppl): 2071s-2077s, 1992
25 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248-254, 1976   DOI   ScienceOn
26 Kim YI. Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomarkers Prev 13: 511-519, 2004
27 Kolhouse JF, Allen RH. Recognition of two intracellular cobalamin binding proteins and their identification as methylmalonyl- CoA mutase and methionine synthetase. Proc Natl Acad Sci USA 74: 921-925, 1977
28 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 81: 440-444, 2005   DOI
29 Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346: 476-483, 2002   DOI   ScienceOn
30 Hoffman DR, Cornatzer WE, Duerre JA. Relationship between tissue levels of S-adenosylmethionine, S-adenylhomocysteine, and transmethylation reactions. Can J Biochem 57: 56-65, 1979   DOI
31 Ho PI, Ashline D, Dhitavat S, Ortiz D, Collins SC, Shea TB, Rogers E. Folate deprivation induces neurodegeneration: roles of oxidative stress and increased homocysteine. Neurobiol Dis 14: 32-42, 2003   DOI   ScienceOn
32 Afman LA, Blom HJ, Drittij MJ, Brouns MR, van Straaten HW. Inhibition of transmethylation disturbs neurulation in chick embryos. Brain Res Dev Brain Res 158: 59-65, 2005   DOI   ScienceOn
33 Zeise ML, Knopfel T, Zieglgansberger W. (+/-)-beta-Parachlorophenylglutamate selectively enhances the depolarizing response to l-homocysteic acid in neocortical neurons of the rat: evidence for a specific uptake system. Brain Res 443: 373-376, 1988   DOI
34 Ghoshal K, Li X, Datta J, Bai S, Pogribny I, Pogribny M, Huang Y, Young D, Jacob ST. A folate- and methyl-deficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of F344 rats. J Nutr 136: 1522-1527, 2006   DOI
35 Regland B, Abrahamsson L, Blennow K, Grenfeldt B, Gottfries CG. CSF-methionine is elevated in psychotic patients. J Neural Transm 111: 631-640, 2004   DOI   ScienceOn
36 Locker J, Reddy TV, Lombardi B. DNA methylation and hepatocarcinogenesis in rats fed a choline-devoid diet. Carcinogenesis 7: 1309-1312, 1986   DOI   ScienceOn
37 Guo Z, Cupples LA, Kurz A, Auerbach SH, Volicer L, Chui H, Green RC, Sadovnick AD, Duara R, DeCarli C, Johnson K, Go RC, Growdon JH, Haines JL, Kukull WA, Farrer LA. Head injury and the risk of AD in the MIRAGE study. Neurology 54: 1316- 1323, 2000   DOI
38 Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr 71: 614S-620S, 2000
39 Lipton SA, Kim WK, Choi YB, Kumar S, D'Emilia DM, Rayudu PV, Arnelle DR, Stamler JS. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA 94: 5923-5928, 1997
40 Seshadri S, Drachman DA, Lippa CF. Apolipoprotein E4 allele and the lifetime risk of Alzheimer's disease. Arch Neurol 52: 1074-1079, 1995   DOI
41 Bird OD, McGlohon VM, Vaitkus JW. A microbiological assay system for naturally occurring folate. Can J Microbiol 15: 465- 472, 1969   DOI   ScienceOn
42 Selhub J, Seyoum E, Pomfret EA. Zeisel SH. Effects of choline deficiency and methotrexate treatment upon liver folate content and distribution. Cancer Res 51: 16-21, 1991
43 Tsai AY, Friedrich CB, Mar MH, Zeisel SH. Choline availability alters embryonic development of the hippocampus and septum in the rat. Brain Res Dev Brain Res 113: 13-20, 1999   DOI
44 Grieve A, Butcher SP, Griffiths R. Synaptosomal plasma membrane transport of excitatory sulphur amino acid transmitter candidates: kinetic characterisation and analysis of carrier specificity. J Neurosci Res 32: 60-68, 1992   DOI   ScienceOn
45 Pomfret EA, daCosta KA, Zeisel SH. Effects of choline deficiency and methotrexate treatment upon rat liver. J Nutr Biochem 1: 533-541, 1990   DOI   ScienceOn
46 Yen CL, Mar MH, Meeker RB, Fernandes A, Zeisel SH. Choline deficiency induces apoptosis in primary cultures of fetal neurons. FASEB J 15: 1704-1710, 2001   DOI   ScienceOn
47 Quinn CT, Griener JC, Bottiglieri T, Arning E, Winick NJ. Effects of intraventricular methotrexate on folate, adenosine, and homocysteine metabolism in cerebrospinal fluid. J Pediatr Hematol Oncol 26: 386-388, 2004   DOI   ScienceOn