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Articles

Lysine-Specific Demethylase 2 Suppresses Lipid Influx and Metabolism in Hepatic Cells

Katsuya Nagaoka, Shinjiro Hino, Akihisa Sakamoto, Kotaro Anan, Ryuta Takase, Takashi Umehara, Shigeyuki Yokoyama, Yutaka Sasaki, Mitsuyoshi Nakao
Katsuya Nagaoka
aDepartment of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
bDepartment of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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Shinjiro Hino
aDepartment of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
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Akihisa Sakamoto
aDepartment of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
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Kotaro Anan
aDepartment of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
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Ryuta Takase
aDepartment of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
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Takashi Umehara
cRIKEN Systems and Structural Biology Center, Yokohama, Japan
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Shigeyuki Yokoyama
cRIKEN Systems and Structural Biology Center, Yokohama, Japan
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Yutaka Sasaki
bDepartment of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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Mitsuyoshi Nakao
aDepartment of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
dCore Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan
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DOI: 10.1128/MCB.01404-14
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ABSTRACT

Cells link environmental fluctuations, such as nutrition, to metabolic remodeling. Epigenetic factors are thought to be involved in such cellular processes, but the molecular basis remains unclear. Here we report that the lysine-specific demethylase 2 (LSD2) suppresses the flux and metabolism of lipids to maintain the energy balance in hepatic cells. Using transcriptome and chromatin immunoprecipitation-sequencing analyses, we revealed that LSD2 represses the genes involved in lipid influx and metabolism through demethylation of histone H3K4. Selective recruitment of LSD2 at lipid metabolism gene loci was mediated in part by a stress-responsive transcription factor, c-Jun. Intriguingly, LSD2 depletion increased the intracellular levels of many lipid metabolites, which was accompanied by an increased susceptibility to toxic cell damage in response to fatty acid exposure. Our data demonstrate that LSD2 maintains metabolic plasticity under fluctuating environment in hepatocytes by mediating the cross talk between the epigenome and metabolism.

FOOTNOTES

    • Received 19 November 2014.
    • Returned for modification 12 December 2014.
    • Accepted 21 January 2015.
    • Accepted manuscript posted online 26 January 2015.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01404-14.

  • Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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Lysine-Specific Demethylase 2 Suppresses Lipid Influx and Metabolism in Hepatic Cells
Katsuya Nagaoka, Shinjiro Hino, Akihisa Sakamoto, Kotaro Anan, Ryuta Takase, Takashi Umehara, Shigeyuki Yokoyama, Yutaka Sasaki, Mitsuyoshi Nakao
Molecular and Cellular Biology Mar 2015, 35 (7) 1068-1080; DOI: 10.1128/MCB.01404-14

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Lysine-Specific Demethylase 2 Suppresses Lipid Influx and Metabolism in Hepatic Cells
Katsuya Nagaoka, Shinjiro Hino, Akihisa Sakamoto, Kotaro Anan, Ryuta Takase, Takashi Umehara, Shigeyuki Yokoyama, Yutaka Sasaki, Mitsuyoshi Nakao
Molecular and Cellular Biology Mar 2015, 35 (7) 1068-1080; DOI: 10.1128/MCB.01404-14
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