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 5

PKA-induced SIRT1 (Ser434) phosphorylation is important for its functional interaction with JMJD3 and PPARα.

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PKA-induced SIRT1 (Ser434) phosphorylation is important for its function...
Hepatocytes were transfected with WT SIRT1 or S434A-SIRT1 expression plasmids for 24 hours and treated with 10 μM Fsk for 30 minutes (A and B), 3 hours (D), or 6 hours (C). (A) p-SIRT1 (Ser434) levels were determined by IP and IB. (B) SIRT1 was immunoprecipitated from whole-cell extracts and JMJD3, PPARα, and CREB levels in the anti-SIRT1 immunoprecipitates from whole-cell lysates were detected by IB. In A and B, consistent results from 2 independent assays were observed. (C) mRNA levels of the indicated genes (n = 6). (D) Occupancy of SIRT1 at the indicated genes (n = 3). (E) Model: Fasting triggers activation of cAMP/PKA signaling, resulting in phosphorylation of SIRT1 at Ser434 and, consequently, the formation of a JMJD3-SIRT1-PPARα complex in hepatocytes, which autoinduces expression of its own genes and epigenetically activates direct SIRT1-targeted β-oxidation, but not gluconeogenic, genes. Epigenetic activation of β-oxidation by the JMJD3-SIRT1-PPARα complex, thus, maintains liver energy balance during fasting. Data represent the mean ± SEM. (C and D) *P < 0.05 and **P < 0.01, by 2-way ANOVA with the FDR test. E, empty.