Gestational Betaine, Liver Metabolism, and Epigenetics

  • Demin Cai
  • Haoyu Liu
  • Yun Hu
  • Yuqian Jiang
  • Ruqian ZhaoEmail author
Reference work entry


Betaine is a methyl donor and a substrate of methionine metabolism. It can donate methyl groups to most of methylation reactions in vivo. Diet low in betaine may greatly contribute to metabolic syndrome, lipid disorders, and diabetes. Recent research studies in the field of metabolic programming have demonstrated that betaine plays critical roles in fetal development and hepatic glucolipid metabolism via an array of complex mechanisms. Liver is a central metabolic organ, which is essential in the control of hepatic glucose, lipid, and cholesterol contents in order to maintain metabolic homeostasis in the whole body. The status of hepatic glucolipid metabolism at newborn stage will eventually affect adult health in a long term. Maternal nutrition programs neonatal hepatic metabolism through epigenetic mechanisms such as DNA methylation, histone modifications, and miRNA-mediated post-transcriptional regulation. Betaine is of critical value in maternal nutritional programming. In this chapter, we provide an overview of the recent advances in studies on the role of maternal betaine on offspring hepatic lipid and glucose metabolism, especially during early life. We hope that this knowledge may shed lights on identifying novel prophylactic and therapeutic strategies for metabolic disorders involving disrupted glucose and lipid homeostasis in human and animals.


Betaine Maternal diet Metabolism Lipid Glucose Cholesterol Metabolic programming Epigenetic Methylation Methionine Histone modification Micro-RNAs 

List of Abbreviations


Acetyl-CoA Carboxylase


S-adenosylhomocysteine hydrolase


Betaine homocysteine methyltransferase






DNA (cytosine-5-)-methyltransferases


Fatty acid synthase


Fructose-1, 6-bisphosphatase




Glycine N-methyltransferase


3-hydroxy-3-methylglutaryl-CoA reductase


Histone methyltransferases




Low-density lipoprotein receptor


Methionine adenosyltransferase


Pyruvate carboxylase


Phosphoenolpyruvate carboxykinase






Stearoyl-CoA desaturase


High-density lipoprotein receptor


Sterol regulatory element-binding protein-1c


Sterol regulatory element binding protein-2




Upstream stimulating factor


  1. Apicella JM, Lee EC, Bailey BL et al (2013) Betaine supplementation enhances anabolic endocrine and Akt signaling in response to acute bouts of exercise. Eur J Appl Physiol 113:793–802CrossRefGoogle Scholar
  2. Benediktsson R, Lindsay RS, Noble J et al (1993) Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 341:339–341CrossRefGoogle Scholar
  3. Cai D, Jia Y, Lu J et al (2014a) Maternal dietary betaine supplementation modifies hepatic expression of cholesterol metabolic genes via epigenetic mechanisms in newborn piglets. Br J Nutr 112:1459–1468CrossRefGoogle Scholar
  4. Cai D, Jia Y, Song H et al (2014b) Betaine supplementation in maternal diet modulates the epigenetic regulation of hepatic gluconeogenic genes in neonatal piglets. PLoS One 9:e105504CrossRefGoogle Scholar
  5. Cai D, Wang J, Jia Y et al (2016a) Gestational dietary betaine supplementation suppresses hepatic expression of lipogenic genes in neonatal piglets through epigenetic and glucocorticoid receptor-dependent mechanisms. Biochim Biophys Acta 1861:41–50CrossRefGoogle Scholar
  6. Cai D, Yuan M, Liu H et al (2016b) Maternal betaine supplementation throughout gestation and lactation modifies hepatic cholesterol metabolic genes in weaning piglets via AMPK/LXR-mediated pathway and histone modification. Nutrients 8:646CrossRefGoogle Scholar
  7. Cong RH, Jia YM, Li RS et al (2012) Maternal low-protein diet causes epigenetic deregulation of HMGCR and CYP7 alpha 1 in the liver of weaning piglets. J Nutr Biochem 23:1647–1654CrossRefGoogle Scholar
  8. Cordero P, Gomez-Uriz AM, Campion J et al (2013) Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet. Genes Nutr 8:105–113CrossRefGoogle Scholar
  9. Donkin SS, Armentano LE (1994) Regulation of gluconeogenesis by insulin and glucagon in the neonatal bovine. Am J Physiol 266:R1229–R1237PubMedGoogle Scholar
  10. Edison RJ, Berg K, Remaley A et al (2007) Adverse birth outcome among mothers with low serum cholesterol. Pediatrics 120:723–733CrossRefGoogle Scholar
  11. Finkelstein JD (2007) Metabolic regulatory properties of S-adenosylmethionine and S-adenosylhomocysteine. Clin Chem Lab Med 45:1694–1699CrossRefGoogle Scholar
  12. Ghaddab-Zroud R, Seugnet I, Steffensen KR et al (2014) Liver X receptor regulation of thyrotropin-releasing hormone transcription in mouse hypothalamus is dependent on thyroid status. PLoS One 9:e106983CrossRefGoogle Scholar
  13. Hu Y, Sun Q, Li X et al (2015) In Ovo injection of betaine affects hepatic cholesterol metabolism through epigenetic gene regulation in newly hatched chicks. PLoS One 10:e0122643CrossRefGoogle Scholar
  14. Huang QC, Xu ZR, Han XY et al (2008) Effect of dietary betaine supplementation on lipogenic enzyme activities and fatty acid synthase mRNA expression in finishing pigs. Anim Feed Sci Technol 140:365–375CrossRefGoogle Scholar
  15. Jia Y, Song H, Gao G et al (2015) Maternal betaine supplementation during gestation enhances expression of mtDNA-encoded genes through D-loop DNA hypomethylation in the skeletal muscle of newborn piglets. J Agric Food Chem 63:10152–10160CrossRefGoogle Scholar
  16. Kathirvel E, Morgan K, Nandgiri G et al (2010) Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: a potential mechanism for hepatoprotection by betaine. Am J Physiol Gastrointest Liver Physiol 299:G1068–G1077CrossRefGoogle Scholar
  17. Kovacheva VP, Mellott TJ, Davison JM et al (2007) Gestational choline deficiency causes global and Igf2 gene DNA hypermethylation by up-regulation of Dnmt1 expression. J Biol Chem 282:31777–31788CrossRefGoogle Scholar
  18. van Lee L, Tint MT, Aris IM et al (2016) Prospective associations of maternal betaine status with offspring weight and body composition at birth: the GUSTO (Growing up in Singapore toward healthy outcomes) cohort study. Am J Clin Nutr 104:1327CrossRefGoogle Scholar
  19. Lever M, Slow S (2010) The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem 43:732–744CrossRefGoogle Scholar
  20. Lever M, Storer MK, Lewis JG et al (2012) Plasma betaine concentrations correlate with plasma cortisol but not with C-reactive protein in an elderly population. Clin Chem Lab Med 50:1635–1640CrossRefGoogle Scholar
  21. Li M, Reynolds CM, Segovia SA et al (2015) Developmental programming of nonalcoholic fatty liver disease: the effect of early life nutrition on susceptibility and disease severity in later life. Biomed Res Int 2015:437107PubMedPubMedCentralGoogle Scholar
  22. Lillycrop KA, Rodford J, Garratt ES et al (2010) Maternal protein restriction with or without folic acid supplementation during pregnancy alters the hepatic transcriptome in adult male rats. Br J Nutr 103:1711–1719CrossRefGoogle Scholar
  23. Matthews JO, Southern LL, Higbie AD et al (2001) Effects of betaine on growth, carcass characteristics, pork quality, and plasma metabolites of finishing pigs. J Anim Sci 79:722–728CrossRefGoogle Scholar
  24. Ross AB, Bruce SJ, Blondel-Lubrano A et al (2011) A whole-grain cereal-rich diet increases plasma betaine, and tends to decrease total and LDL-cholesterol compared with a refined-grain diet in healthy subjects. Br J Nutr 105:1492–1502CrossRefGoogle Scholar
  25. Schaefer-Graf UM, Graf K, Kulbacka I et al (2008) Maternal lipids as strong determinants of fetal environment and growth in pregnancies with gestational diabetes mellitus. Diabetes Care 31:1858–1863CrossRefGoogle Scholar
  26. Schwab U, Torronen 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 76:961–967CrossRefGoogle Scholar
  27. Sohi G, Marchand K, Revesz A et al (2011) Maternal protein restriction elevates cholesterol in adult rat offspring due to repressive changes in histone modifications at the cholesterol 7 alpha-hydroxylase promoter. Mol Endocrinol 25:785–798CrossRefGoogle Scholar
  28. Sram RJ, Binkova B, Lnenickova Z et al (2005) The impact of plasma folate levels of mothers and newborns on intrauterine growth retardation and birth weight. Mutat Res 591:302–310CrossRefGoogle Scholar
  29. Vo T, Hardy DB (2012) Molecular mechanisms underlying the fetal programming of adult disease. J Cell Commun Signal 6:139–153CrossRefGoogle Scholar
  30. Yang CP, Wang HA, Tsai TH et al (2012) Characterization of the neuropsychological phenotype of glycine N-methyltransferase−/− mice and evaluation of its responses to clozapine and sarcosine treatments. Eur Neuropsychopharmacol 22:596–606CrossRefGoogle Scholar
  31. Yu CY, Mayba O, Lee JV et al (2010) Genome-wide analysis of glucocorticoid receptor binding regions in adipocytes reveal gene network involved in triglyceride homeostasis. PLoS One 5:e15188CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Demin Cai
    • 1
  • Haoyu Liu
    • 2
  • Yun Hu
    • 1
  • Yuqian Jiang
    • 3
  • Ruqian Zhao
    • 1
    Email author
  1. 1.Key Laboratory of Animal Physiology and Biochemistry, Ministry of AgricultureCollege of Veterinary Medicine, Nanjing Agricultural UniversityNanjingChina
  2. 2.Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
  3. 3.Department of Biochemistry and Molecular MedicineUniversity of California at DavisSacramentoUSA

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