Journal
DIABETES
Volume 64, Issue 3, Pages 775-784Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db14-0158
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Ministry of Health, Labor, and Welfare of Japan
- Ono Medical Foundation
- Naito Foundation
- Nestle Nutrition Council, Japan
- Grants-in-Aid for Scientific Research [26350884] Funding Source: KAKEN
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The metabolic function of the liver changes sequentially during early life in mammals to adapt to the marked changes in nutritional environment. Accordingly, hepatic fatty acid -oxidation is activated after birth to produce energy from breast milk lipids. However, how it is induced during the neonatal period is poorly understood. Here we show DNA demethylation and increased mRNA expression of the fatty acid -oxidation genes in the postnatal mouse liver. The DNA demethylation does not occur in the fetal mouse liver under the physiologic condition, suggesting that it is specific to the neonatal period. Analysis of mice deficient in the nuclear receptor peroxisome proliferator-activated receptor (PPAR) and maternal administration of a PPAR ligand during the gestation and lactation periods reveal that the DNA demethylation is PPAR dependent. We also find that DNA methylation of the fatty acid -oxidation genes are reduced in the adult human liver relative to the fetal liver. This study represents the first demonstration that the ligand-activated PPAR-dependent DNA demethylation regulates the hepatic fatty acid -oxidation genes during the neonatal period, thereby highlighting the role of a lipid-sensing nuclear receptor in the gene- and life-stage-specific DNA demethylation of a particular metabolic pathway.
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