Effect of acute hyperhomocysteinemia on methylation potential of erythrocytes and on DNA methylation of lymphocytes in healthy male volunteers

Fux, Richard; Kloor, Doris; Hermes, Marina; Rock, Thomas; Proksch, Barbara; Grenz, Almut; Delabar, Ursula; Bücheler, R.; Igel, Svitlana; Mörike, Klaus; Ch, Gleiter; Oßwald, Hartmut

doi:10.1152/ajprenal.00465.2004

Cited by 31 publications

(26 citation statements)

References 34 publications

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“…This is in contrast to our previous report that dietinduced HHcy in Cbs +/-mice is associated with higher AdoHcy concentrations and lower AdoMet/AdoHcy ratios in brain. 11 Furthermore, a study by another group reported higher concentrations of AdoMet and AdoHcy but no differences in AdoMet/ AdoHcy ratios in brain from Cbs +/-mice with diet-induced reported in human subjects following an oral L-homocysteine load, 14 an effect most likely explained by timing with an acute short-term elevation in plasma total homocysteine and AdoHcy concentrations insufficient to affect DNA methylation.…”

Section: Discussionmentioning

confidence: 97%

Tissue-specific relationship of S-adenosylhomocysteine with allele-specificH19/Igf2methylation and imprinting in mice with hyperhomocysteinemia

et al. 2013

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osteoporosis3,4 and depression. 5 The molecular mechanisms contributing to HHcy-related pathologies are not fully known but may involve several pathways including gene-specific changes in DNA methylation. Homocysteine is metabolically-linked to cellular methylation reactions through the methionine cycle. Within the cycle, methionine is converted to S-adenosylmethionine (AdoMet), which serves as a methyl donor for numerous methyl acceptors, including phospholipids, DNA, RNA and proteins. S-adenosylhomocysteine (AdoHcy) is produced as a byproduct of methyl donation, and homocysteine is formed through the DNa methylation is linked to homocysteine metabolism through the generation of S-adenosylmethionine (adoMet) and S-adenosylhomocysteine (adohcy). The ratio of adoMet/adohcy is often considered an indicator of tissue methylation capacity. The goal of this study is to determine the relationship of tissue adoMet and adohcy concentrations to allele-specific methylation and expression of genomically imprinted H19/Igf2. Expression of H19/Igf2 is regulated by a differentially methylated domain (DMD), with H19 paternally imprinted and Igf2 maternally imprinted. F1 hybrid c57BL/6J x Castaneous/EiJ (Cast) mice with (+/-), and without (+/+), heterozygous disruption of cystathionine-β-synthase (Cbs) were fed a control diet or a diet (called hh) to induce hyperhomocysteinemia and changes in tissue adoMet and adohcy. F1 Cast x Cbs +/-mice fed the hh diet had significantly higher plasma total homocysteine concentrations, higher liver adohcy, and lower adoMet/adohcy ratios and this was accompanied by lower liver maternal H19 DMD allele methylation, lower liver Igf2 mRNa levels, and loss of Igf2 maternal imprinting. In contrast, we found no significant differences in adoMet and adohcy in brain between the diet groups but F1 Cast x Cbs +/-mice fed the hh diet had higher maternal H19 DMD methylation and lower H19 mRNa levels in brain. a significant negative relationship between adohcy and maternal H19 DMD allele methylation was found in liver but not in brain. These findings suggest the relationship of adoMet and adohcy to gene-specific DNa methylation is tissue-specific and that changes in DNa methylation can occur without changes in adoMet and adohcy.

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Section: Discussionmentioning

confidence: 97%

Tissue-specific relationship of S-adenosylhomocysteine with allele-specificH19/Igf2methylation and imprinting in mice with hyperhomocysteinemia

et al. 2013

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“…Hepatic Methionine Metabolism-Dietary restriction of protein resulted in a higher rate of transmethylation of methionine, higher methylation potential (higher AdoMet/AdoHcy ratio) (48), lower activity of cystathionine ␤-synthase and cystathionine ␥-lyase, as well as a higher level of expression of cysteinesulfinic acid decarboxylase and glutamate-cysteine ligase. These changes were associated with lower hepatic cysteine and taurine levels and no alteration in the concentration of homocysteine and glutathione.…”

Section: Discussionmentioning

confidence: 99%

Metabolic and Genomic Response to Dietary Isocaloric Protein Restriction in the Rat

Kalhan¹,

Uppal²,

Moorman³

et al. 2011

Journal of Biological Chemistry

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We have examined hepatic, genomic, and metabolic responses to dietary protein restriction in the non-pregnant Sprague-Dawley rat. Animals were pair-fed either a 6 or 24% casein-based diet for 7-10 days. At the end of the dietary period, a microarray analysis of the liver was performed, followed by validation of the genes of interest. The rates of appearance of phenylalanine, methionine, serine, and glucose and the contribution of pyruvate to serine and glucose were quantified using tracer methods. Plasma and tissue amino acid levels, enzyme activities, and metabolic intermediates were measured. Protein restriction resulted in significant differential expression of a number of genes involved in cell cycle, cell differentiation, transport, transcription, and metabolic processes. RT-PCR showed that the expression of genes involved in serine biosynthesis and fatty acid oxidation was higher, and those involved in fatty acid synthesis and urea synthesis were lower in the liver of protein-restricted animals. Free serine and glycine levels were higher and taurine levels lower in all tissues examined. Tracer isotope studies showed an ϳ50% increase in serine de novo synthesis. Pyruvate was the primary (ϳ90%) source of serine in both groups. Transmethylation of methionine was significantly higher in the protein-restricted group. This was associated with a higher S-adenosylmethionine/Sadenosylhomocysteine ratio and lower cystathione ␤-synthase and cystathionine ␥-lyase activity. Dietary isocaloric protein restriction results in profound changes in hepatic one-carbon metabolism within a short period. These may be related to high methylation demands placed on the organism and caused by possible changes in cellular osmolarity as a result of the efflux of the intracellular taurine.The metabolic and biochemical impact of qualitative and quantitative changes in dietary protein intake continues to be of interest because of their implications for public health and because of a number of studies showing a strong relationship between protein intake during pregnancy with cardiovascular function, hypertension, and glucose intolerance in the offspring (1-3). Studies in humans, primarily focused on whole body protein, nitrogen metabolism, and protein accretion, show that both high and low protein intake can impact these processes (4 -7). However, how humans adapt to protein deprivation or the biochemical mechanisms involved has not been examined. In the context of pregnancy, both high protein intake (in humans) and protein restriction in rodents have been shown to cause fetal metabolic programming and consequently altered physiological response in the offspring in adulthood (8 -11). In the rodent, dietary protein restriction during pregnancy results in growth retardation, impaired beta cell function and mass, impaired insulin sensitivity, hypertension, and other pathological responses in the offspring (1, 2). These have been associated with a change in the hypothalamic-pituitary-adrenal axis, changes in the renin-angiotensin system, and ...

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“…The increased AdoHcy concentration was mainly associated with global DNA hypomethylation [18][19][20]. On the other hand, short term changes in MP or transient Hcy elevation do not change global DNA methylation suggesting that the differential gene expression is not associated with changes of methylation pattern of the DNA [22,36]. Therefore, we suggest that the lowered EPO expression during HHcy might be the result of inhibition of mRNA methylation.…”

Section: Discussionmentioning

confidence: 75%

Hyperhomocysteinemia is Associated with Decreased Erythropoietin Expression in Rats

Grenz

Hermes

Hammel

et al. 2010

Cell Physiol Biochem

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Background/Aims: Elevated plasma homocysteine (Hcy) levels have been identified as a pathogenic factor causing a variety of pathological changes in different cells and tissues. In vertebrates, Hcy is produced solely from S-adenosylhomocysteine (AdoHcy) through the catalysis of AdoHcy-hydrolase. The direction of AdoHcy-hydrolase activity is determined by its cytosolic substrate concentrations, thereby controlling intracellular AdoHcy levels. Most S-adenosylmethionine (AdoMet)-dependent methyltransferases are regulated in vivo by the ratio of AdoMet/AdoHcy, which is termed “methylation potential” (MP). To test whether high rates of erythropoietin (EPO) expression is reduced by a low MP in vivo we choosed the model of increased EPO production following carbon monoxide (CO) exposure in rats in which high transcriptional activity is responsible for renal EPO production. Results: To induce a sustained hyperhomocysteinemia in rats, we infused i.v. a low or high dose of Hcy resulting in Hcy plasma levels of 87.4±6.2 and 300.8±23.7 µmol/l, respectively. Renal tissue contents of AdoHcy, AdoMet, and adenosine (Ado) were measured after freeze clamp by means of HPLC. Within 4h of CO exposure EPO serum levels increased from 13.6±0.4 (control) to 2254.8±278.3 mIU/ml. Only high dose of Hcy reduces both, the MP from 40.8±2.0 to 8.2±1.0 in the kidney as well as EPO serum levels by 40% compared to control rats. Conclusion: Our data show that severe hyperhomocysteinemia (HHcy) affects the MP in the renal tissue and lowers EPO expression following CO induced intoxication. This result supports the concept that efficient EPO production requires an unimpaired MP.

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Effect of acute hyperhomocysteinemia on methylation potential of erythrocytes and on DNA methylation of lymphocytes in healthy male volunteers

Cited by 31 publications

References 34 publications

Tissue-specific relationship of S-adenosylhomocysteine with allele-specificH19/Igf2methylation and imprinting in mice with hyperhomocysteinemia

Tissue-specific relationship of S-adenosylhomocysteine with allele-specificH19/Igf2methylation and imprinting in mice with hyperhomocysteinemia

Metabolic and Genomic Response to Dietary Isocaloric Protein Restriction in the Rat

Hyperhomocysteinemia is Associated with Decreased Erythropoietin Expression in Rats

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