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Epigenetic Switching and Neonatal Nutritional Environment

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

Abstract

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.

Keywords

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

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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

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