Effects of Betaine Supplementation and Choline Deficiency on Folate Deficiency-Induced Hyperhomocysteinemia in Rats

Liu, Ying; Liu, Yiqun; Morita, Tatsuya; Sugiyama, Kimio

doi:10.3177/jnsv.58.69

Cited by 6 publications

(5 citation statements)

References 46 publications

(43 reference statements)

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“…This presumption was supported by the significant up-regulation of BHMT, GNMT and DNMT1 at both mRNA and protein levels in the hippocampus of prenatally betaine-supplemented piglets. Our results support the previous finding that betaine supplementation causes BHMT up-regulation [46]. However, there is scarcely any literature concerning the alterations of methyltransferases, such as GNMT and DNMT1, in response to maternal betaine treatment.…”

Section: Discussionsupporting

confidence: 94%

Dietary betaine supplementation to gestational sows enhances hippocampal IGF2 expression in newborn piglets with modified DNA methylation of the differentially methylated regions

Sun

et al. 2014

Eur J Nutr

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Section: Discussionsupporting

confidence: 94%

Dietary betaine supplementation to gestational sows enhances hippocampal IGF2 expression in newborn piglets with modified DNA methylation of the differentially methylated regions

Sun

et al. 2014

Eur J Nutr

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“…Previous investigations demonstrate that betaine supplementation causes BHMT up-regulation [35], [36]. However, in this study, all the three key enzymes involved in methionine metabolism, BHMT, MAT2B and AHCYL1, were up-regulated in the liver of newborn betaine-exposed piglets.…”

Section: Discussioncontrasting

confidence: 76%

Betaine Supplementation in Maternal Diet Modulates the Epigenetic Regulation of Hepatic Gluconeogenic Genes in Neonatal Piglets

Cai

Jia

et al. 2014

PLoS ONE

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In this study, gestational sows were fed control or betaine-supplemented diets (3 g/kg) throughout the pregnancy, and the newborn piglets were used to elucidate whether maternal dietary betaine affected offspring hepatic gluconeogenic genes through epigenetic mechanisms. Neonatal piglets born to betaine-supplemented sows had significantly higher serum and hepatic betaine contents, together with significantly greater expression of methionine metabolic enzymes in the liver. Interestingly, significantly higher serum concentrations of lactic acid and glucogenic amino acids, including serine, glutamate, methionine and histidine, were detected in the piglets born to betaine-supplemented sows, which were coincident with higher hepatic glycogen content and PEPCK1 enzyme activity, as well as greater protein expression of gluconeogenic enzymes, pyruvate carboxylase (PC), cytoplasmic phosphoenolpyruvate carboxykinase (PEPCK1), mitochondrional phosphoenolpyruvate carboxykinase (PEPCK2) and fructose-1, 6-bisphosphatase (FBP1). Moreover, maternal betaine significantly changed the methylation status of both CpGs and histones on the promoter of gluconeogenic genes. The lower PEPCK1 mRNA was associated with DNA hypermethylation and more enriched repression histone mark H3K27me3, while the up-regulated PEPCK2 and FBP1 mRNA was associated with DNA hypomethylation and more enriched activation histone mark H3K4me3. Furthermore, the expression of two miRNAs predicted to target PC and 6 miRNAs predicted to target PEPCK1 was dramatically suppressed in the liver of piglets born to betaine-supplemented sows. Our results provide the first evidence that maternal betaine supplementation affects hepatic gluconeogenic genes expression in newborn piglets through enhanced hepatic methionine metabolism and epigenetic regulations, which involve DNA and histone methylations, and possibly miRNAs-mediated post-transcriptional mechanism.

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“…However, in cells with an active transsulfuration pathway, such as hepatocytes, an increase in Hcy levels causes an increase in the CBS reaction rate, providing an additional sink for Hcy and diminishing the elevation of [Hcy] relative to cells that lack this pathway. Thus, the simulation results strongly suggest that the increase in plasma Hcy levels observed in cases of folate deficiency 35,36 is due to tissues other than liver.…”

Section: Resultsmentioning

confidence: 77%

“…1), and elevated Hcy levels in blood plasma are associated with cardiovascular diseases and other pathologies 5,57 . Interestingly, the concentration of Hcy is lower in the liver than in plasma 35,36,58,59 , and in the case of folate deficiency, liver [Hcy] increases much less than plasma [Hcy] 35,36 . Liver cells have a highly active transsulfuration pathway that can efficiently clear intracellular Hcy.…”

Section: Resultsmentioning

confidence: 99%

Rat liver folate metabolism can provide an independent functioning of associated metabolic pathways

Зайцев

Martinov

Vitvitsky

et al. 2019

Sci Rep

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Folate metabolism in mammalian cells is essential for multiple vital processes, including purine and pyrimidine synthesis, histidine catabolism, methionine recycling, and utilization of formic acid. It remains unknown, however, whether these processes affect each other via folate metabolism or can function independently based on cellular needs. We addressed this question using a quantitative mathematical model of folate metabolism in rat liver cytoplasm. Variation in the rates of metabolic processes associated with folate metabolism (i.e., purine and pyrimidine synthesis, histidine catabolism, and influxes of formate and methionine) in the model revealed that folate metabolism is organized in a striking manner that enables activation or inhibition of each individual process independently of the metabolic fluxes in others. In mechanistic terms, this independence is based on the high activities of a group of enzymes involved in folate metabolism, which efficiently maintain close-to-equilibrium ratios between substrates and products of enzymatic reactions.

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Effects of Betaine Supplementation and Choline Deficiency on Folate Deficiency-Induced Hyperhomocysteinemia in Rats

Cited by 6 publications

References 46 publications

Dietary betaine supplementation to gestational sows enhances hippocampal IGF2 expression in newborn piglets with modified DNA methylation of the differentially methylated regions

Dietary betaine supplementation to gestational sows enhances hippocampal IGF2 expression in newborn piglets with modified DNA methylation of the differentially methylated regions

Betaine Supplementation in Maternal Diet Modulates the Epigenetic Regulation of Hepatic Gluconeogenic Genes in Neonatal Piglets

Rat liver folate metabolism can provide an independent functioning of associated metabolic pathways

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