title: Lysine-specific demethylase 2 suppresses lipid influx and metabolism in hepatic cells.
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.
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nagaoka
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan s-hino@kumamoto-u.ac.jp mnakao@gpo.kumamoto-u.ac.jp.
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Hino
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Anan
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Takase
authors.affiliation: RIKEN Systems and Structural Biology Center, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Umehara
authors.affiliation: RIKEN Systems and Structural Biology Center, Yokohama, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan s-hino@kumamoto-u.ac.jp mnakao@gpo.kumamoto-u.ac.jp.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
mesh_terms: D000818:Animals; D015536:Down-Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D008810:Mice, Inbred C57BL; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism
chemical_list: D006657:Histones; D008055:Lipids; D016755:Proto-Oncogene Proteins c-jun; D056466:Histone Demethylases; C000595993:KDM1B protein, human; D008239:Lysine