| First Author | Seok S | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 7 | Pages | 3144-3159 |
| PubMed ID | 29911994 | Mgi Jnum | J:265480 |
| Mgi Id | MGI:6197673 | Doi | 10.1172/JCI97736 |
| Citation | Seok S, et al. (2018) Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid beta-oxidation. J Clin Invest 128(7):3144-3159 |
| abstractText | Jumonji D3 (JMJD3) histone demethylase epigenetically regulates development and differentiation, immunity, and tumorigenesis by demethylating a gene repression histone mark, H3K27-me3, but a role for JMJD3 in metabolic regulation has not been described. SIRT1 deacetylase maintains energy balance during fasting by directly activating both hepatic gluconeogenic and mitochondrial fatty acid beta-oxidation genes, but the underlying epigenetic and gene-specific mechanisms remain unclear. In this study, JMJD3 was identified unexpectedly as a gene-specific transcriptional partner of SIRT1 and epigenetically activated mitochondrial beta-oxidation, but not gluconeogenic, genes during fasting. Mechanistically, JMJD3, together with SIRT1 and the nuclear receptor PPARalpha, formed a positive autoregulatory loop upon fasting-activated PKA signaling and epigenetically activated beta-oxidation-promoting genes, including Fgf21, Cpt1a, and Mcad. Liver-specific downregulation of JMJD3 resulted in intrinsic defects in beta-oxidation, which contributed to hepatosteatosis as well as glucose and insulin intolerance. Remarkably, the lipid-lowering effects by JMJD3 or SIRT1 in diet-induced obese mice were mutually interdependent. JMJD3 histone demethylase may serve as an epigenetic drug target for obesity, hepatosteatosis, and type 2 diabetes that allows selective lowering of lipid levels without increasing glucose levels. |
