Epigenetic Switching and Neonatal Nutritional Environment

  • Koshi HashimotoEmail author
  • Yoshihiro Ogawa
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1012)


The hepatic metabolic function changes sequentially during early life in mammals to adapt to the drastic changes in the nutritional environment. Accordingly, hepatic fatty acid β-oxidation is activated after birth to produce energy from breast milk lipids. De novo lipogenesis is induced upon the onset of oral intake, when the major nutritional source switches to carbohydrate. However, how a particular metabolic pathway is activated during the liver maturation is poorly understood. We found that the expression of glycerol-3-phosphate acyltransferase 1 (GPAT1), a rate-limiting enzyme of de novo hepatic lipogenesis, is epigenetically regulated in the mouse liver by DNA methylation. In the neonatal liver, DNA methylation of the GPAT1 gene (Gpam) promoter, which is likely to be induced by DNA methyltransferase (Dnmt) 3b, inhibited the recruitment of sterol regulatory element-binding protein-1c (SREBP-1c), whereas in the adult, decreased DNA methylation resulted in active chromatin conformation, allowing the recruitment of SREBP-1c. Maternal nutritional environment affects the DNA methylation status in the Gpam promoter, GPAT1 expression, and triglyceride content in the liver of the offspring. We also found DNA demethylation and increased mRNA expression of the fatty acid β-oxidation genes in the postnatal mouse liver. The DNA demethylation is specifically induced in the lactation period. Analysis of mice deficient in the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and maternal administration of a PPARα ligand during the gestation and lactation periods reveals that the DNA demethylation is PPARα-dependent. These findings indicate the gene- and lifestage-specific DNA demethylation of a particular metabolic pathway in the neonatal liver to adapt the marked changes in nutritional environment in early life.


DNA demethylation De novo lipogenesis GPAT1 SREBP-1c Dnmt3b Fatty acid β-oxidation PPARα 


  1. 1.
    Perez-Castillo A, Schwartz HL, Oppenheimer JH. Rat hepatic mRNA-S14 and lipogenic enzymes during weaning: role of S14 in lipogenesis. Am J Phys. 1987;253:E536–42.Google Scholar
  2. 2.
    Decaux JF, Ferré P, Robin D, Robin P, Girard J. Decreased hepatic fatty acid oxidation at weaning in the rat is not linked to a variation of malonyl-CoA concentration. J Biol Chem. 1988;263:3284–9.PubMedGoogle Scholar
  3. 3.
    Wendel AA, Lewin TM, Coleman RA. Glycerol-3-phosphate acyltransferases: rate limiting enzymes of triacylglycerol biosynthesis. Biochim Biophys Acta. 1791;2009:501–6.Google Scholar
  4. 4.
    Lindén D, William-Olsson L, Ahnmark A, et al. Liver-directed overexpression of mitochondrial glycerol-3-phosphate acyltransferase results in hepatic steatosis, increased triacylglycerol secretion and reduced fatty acid oxidation. FASEB J. 2006;20:434–43.CrossRefPubMedGoogle Scholar
  5. 5.
    Hammond LE, Gallagher PA, Wang S, et al. Mitochondrial glycerol-3-phosphate acyltransferase-deficient mice have reduced weight and liver triacylglycerol content and altered glycerolipid fatty acid composition. Mol Cell Biol. 2002;22:8204–14.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ericsson J, Jackson SM, Kim JB, Spiegelman BM, Edwards PA. Identification of glycerol-3-phosphate acyltransferase as an adipocyte determination and differentiation factor 1- and sterol regulatory element-binding protein responsive gene. J Biol Chem. 1997;272:7298–305.CrossRefPubMedGoogle Scholar
  7. 7.
    Tabor DE, Kim JB, Spiegelman BM, Edwards PA. Identification of conserved cis-elements and transcription factors required for sterol-regulated transcription of stearoyl-CoA desaturase 1 and 2. J Biol Chem. 1999;274:20603–10.CrossRefPubMedGoogle Scholar
  8. 8.
    Wong RH, Chang I, Hudak CS, Hyun S, Kwan HY, Sul HS. A role of DNA-PK for the metabolic gene regulation in response to insulin. Cell. 2009;136:1056–72.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247–57.CrossRefPubMedGoogle Scholar
  10. 10.
    Weber M, Hellmann I, Stadler MB, et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet. 2007;39:457–66.CrossRefPubMedGoogle Scholar
  11. 11.
    Mikkelsen TS, Xu Z, Zhang X, et al. Comparative epigenomic analysis of murine and human adipogenesis. Cell. 2010;143:156–69.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Maunakea AK, Nagarajan RP, Bilenky M, et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010;466:253–7.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Sharif J, Muto M, Takebayashi S, et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 2007;450:908–12.CrossRefPubMedGoogle Scholar
  14. 14.
    Ehara T, Kamei Y, Takahashi M, et al. Role of DNA methylation in the regulation of lipogenic glycerol-3-phosphate acyltransferase 1 gene expression in the mouse neonatal liver. Diabetes. 2012;61:2442–50.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kato Y, Kaneda M, Hata K, et al. Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse. Hum Mol Genet. 2007;16:2272–80.CrossRefPubMedGoogle Scholar
  16. 16.
    Ehara T, Kamei Y, Yuan X, et al. Ligand-activated PPARα-dependent DNA demethylation regulates the fatty acid β-oxidation genes in the postnatal liver. Diabetes. 2015;64:775–84.CrossRefPubMedGoogle Scholar
  17. 17.
    Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest. 2006;116:571–80.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rakhshandehroo M, Knoch B, Muller M, Kersten S. Peroxisome proliferator activated receptor alpha target genes. PPAR Res. 2010;2010Google Scholar
  19. 19.
    Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature. 2000;405:421–4.CrossRefPubMedGoogle Scholar
  20. 20.
    Lee SS, Pineau T, Drago J, et al. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 1995;15:3012–22.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Périchon R, Bourre JM. Peroxisomal beta-oxidation activity and catalase activity during development and aging in mouse liver. Biochimie. 1995;77:288–93.CrossRefPubMedGoogle Scholar
  22. 22.
    Gluckman PD, Hanson MA, Buklijas T, Low FM, Beedle AS. Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol. 2009;5:401–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Preemptive Medicine and MetabolismTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
  3. 3.Department of Medicine and Bioregulatory Science, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  4. 4.AMED, CRESTTokyoJapan

Personalised recommendations