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Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation
Sunmi Seok, … , Byron Kemper, Jongsook Kim Kemper
Sunmi Seok, … , Byron Kemper, Jongsook Kim Kemper
Published June 18, 2018
Citation Information: J Clin Invest. 2018;128(7):3144-3159. https://doi.org/10.1172/JCI97736.
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Research Article Cell biology Metabolism Article has an altmetric score of 14

Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation

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Abstract

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 β-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 β-oxidation, but not gluconeogenic, genes during fasting. Mechanistically, JMJD3, together with SIRT1 and the nuclear receptor PPARα, formed a positive autoregulatory loop upon fasting-activated PKA signaling and epigenetically activated β-oxidation–promoting genes, including Fgf21, Cpt1a, and Mcad. Liver-specific downregulation of JMJD3 resulted in intrinsic defects in β-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.

Authors

Sunmi Seok, Young-Chae Kim, Sangwon Byun, Sunge Choi, Zhen Xiao, Naoki Iwamori, Yang Zhang, Chaochen Wang, Jian Ma, Kai Ge, Byron Kemper, Jongsook Kim Kemper

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Figure 8

JMJD3-mediated lipid-lowering effects in HFD obese mice are attenuated by downregulation of SIRT1.

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JMJD3-mediated lipid-lowering effects in HFD obese mice are attenuated b...
(A) Mice that had been fed a HFD or normal diet (ND) for 12 weeks were fasted for 16 hours or re-fed for 6 hours after fasting. Hepatic JMJD3 levels were determined by IB (n = 3). (B–I) Mice were fed a HFD for 12 weeks or ND and injected with the indicated viruses for 4 weeks. (B) Experimental outline and hepatic JMJD3 and SIRT1 levels. (C) Liver sections were stained as indicated. Scale bar: 100 μm. (D) Liver TG levels. (E) Blood glucose levels were determined by GTT. (F) mRNA levels of the indicated genes. (G) Palmitate oxidation rates were determined in liver extracts. (H) Liver acylcarnitine levels. (I) Serum β-hydroxybutyrate levels. Data represent the mean ± SEM. n = 5–6. *P < 0.05 and **P < 0.01, by 1-way ANOVA with the FDR test (D–I). E, empty.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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