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 July 2, 2018; First 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 1

JMJD3 is a SIRT1-interacting protein.

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JMJD3 is a SIRT1-interacting protein. (A) Proteins in HepG2 cells associ...
(A) Proteins in HepG2 cells associated with exogenously expressed flag-SIRT1 (f-SIRT1) were analyzed by LC-MS, and the spectrum identifying a JMJD3 peptide is shown. IB shows interaction of the indicated proteins with flag-SIRT1 detected by co-IP. Ad, adenovirus. (B) Adenovirally expressed flag-SIRT1 was isolated by binding the M2 agarose from liver extracts pooled from 3 mice and analyzed by glycerol gradient (10%–50%) centrifugation. The indicated proteins were detected by IB. (C) Mice (n = 3) were fasted for 16 hours. SIRT1 or JMJD3 was immunoprecipitated from whole-cell extracts, and the levels of JMJD3 or SIRT1 in the immunoprecipitates were determined by IB. (D) JMJD3 and SIRT1 levels in nuclear and cytoplasmic fractions of liver extracts from mice re-fed for 6 hours after fasting and mice fasted for 16 hours. (E) Detection of JMJD3 and SIRT1 by immunofluorescence in liver sections from mice re-fed for 6 hours after fasting and mice fasted for 16 hours. Scale bars: 100 μm (white bars) and 20 μm (yellow bars). Original magnification ×2.5. (F) GST-JMJD3 and GST-SIRT1 constructs are shown. SIRT1 or JMJD3, synthesized in vitro by TNT, was incubated with the GST fusion proteins, and proteins bound to the GST fusion proteins were detected by IB. FL, full length. fd, mice re-fed for 6 hours after fasting; fs, mice fasted for 16 hours.