Ligand-Activated PPARα-Dependent DNA Demethylation Regulates the Fatty Acid β-Oxidation Genes in the Postnatal Liver
| Autor: | Hitoshi Shimano, Kazutaka Tsujimoto, Tatsuya Ehara, Yasutomi Kamei, Mayumi Takahashi, Takashi Tamiya, Takayoshi Suganami, Yoshihiro Ogawa, Izuho Hatada, Erina Tamura, Koshi Hashimoto, Yoshimi Nakagawa, Sayaka Kanai, Xunmei Yuan, Takako Takai-Igarashi |
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| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Endocrinology Diabetes and Metabolism Blotting Western Biology Mice Internal medicine Internal Medicine medicine Animals PPAR alpha Receptor Gene Triglycerides Oligonucleotide Array Sequence Analysis chemistry.chemical_classification Fatty Acids Fatty acid DNA Methylation Peroxisome Mice Inbred C57BL Metabolic pathway DNA demethylation Endocrinology Liver chemistry Nuclear receptor DNA methylation Female Oxidation-Reduction |
| Zdroj: | Diabetes. 64:775-784 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db14-0158 |
| Popis: | 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 α (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 life-stage–specific DNA demethylation of a particular metabolic pathway. |
| Databáze: | OpenAIRE |
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