Ligand-activated PPARα-dependent DNA demethylation regulates the fatty acid β-oxidation genes in the postnatal liver

Tatsuya Ehara, Yasutomi Kamei, Xunmei Yuan, Mayumi Takahashi, Sayaka Kanai, Erina Tamura, Kazutaka Tsujimoto, Takashi Tamiya, Yoshimi Nakagawa, Hitoshi Shimano, Takako Takai-Igarashi, Izuho Hatada, Takayoshi Suganami, Koshi Hashimoto, Yoshihiro Ogawa

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


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 β-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 β-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 a (PPARα) and maternal administration of a PPARα ligand during the gestation and lactation periods reveal that the DNA demethylation is PPARα dependent. We also find that DNA methylation of the fatty acid β-oxidation genes are reduced in the adult human liver relative to the fetal liver. This study represents the first demonstration that the ligand-activated PPARα-dependent DNA demethylation regulates the hepatic fatty acid β-oxidation genes during the neonatal period, thereby highlighting the role of a lipid-sensing nuclear receptor in the gene- and lifestage- specific DNA demethylation of a particular metabolic pathway.

Original languageEnglish
Pages (from-to)775-784
Number of pages10
Issue number3
Publication statusPublished - Mar 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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