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

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

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 3

Fasting-induced interaction of JMJD3 with SIRT1 and PPARα is important for recruitment of JMJD3 to β-oxidation genes.

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Fasting-induced interaction of JMJD3 with SIRT1 and PPARα is important f...
(A) Mice were fasted for 16 hours or re-fed for 6 hours after fasting (n = 3), and co-IP assays were performed using liver whole-cell extracts. (B) Schematic diagrams of PPARα domains (top). JMJD3 and SIRT1 bound to GST-PPARα proteins were detected by IB (bottom). (C) Chromatin from livers of fasted mice was immunoprecipitated with PPARα antibody, eluted, and reprecipitated with SIRT1 or JMJD3 antibody (n = 3). (D) Hepa1c1c7 cells were transfected with the indicated plasmids and infected with shRNA and then treated with the PPARα ligand WY14643 overnight, followed by treatment with Fsk for 6 hours. Relative luciferase activity was normalized to β-gal activity. (E) Hepatocytes were infected with Ad-shSIRT1 or Ad-shCtl for 48 hours or transfected with siPPARα or control siRNA for 48 hours and treated with Fsk for 3 hours. Occupancy of JMJD3 at the indicated genes was determined by ChIP assay (n = 3). (F) C57BL6 and PPARα-KO mice were fasted for 24 hours or re-fed for 24 hours after fasting. Occupancy of JMJD3 at the indicated genes was determined by ChIP assay (n = 5). Data represent the mean ± SEM. **P < 0.01, by Mann-Whitney U test (C) or 2-way ANOVA with the FDR test (E and F).