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

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

  2. Author Address

    Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka, Japan., Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA.,
    1. Year: 2018
    2. Date: Jul 2
    3. Epub Date: 2018 06 18
  2. Journal: The Journal of Clinical Investigation
    1. 128
    2. 7
    3. Pages: 3144-3159
  4. Type of Article: Article
  5. ISSN: 0021-9738
  1. 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 ß-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 ß-oxidation, but not gluconeogenic, genes during fasting. Mechanistically, JMJD3, together with SIRT1 and the nuclear receptor PPARa, formed a positive autoregulatory loop upon fasting-activated PKA signaling and epigenetically activated ß-oxidation-promoting genes, including Fgf21, Cpt1a, and Mcad. Liver-specific downregulation of JMJD3 resulted in intrinsic defects in ß-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.

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External Sources

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  2. DOI: 10.1172/JCI97736
  3. PMID: 29911994
  4. View record in Web of Science®
  5. WOS: 000437234600043
  6. PII : 97736

Library Notes

  1. Fiscal Year: FY2017-2018
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