title: FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure.
abstract: Environmental factors such as nutritional state may act on the epigenome that consequently contributes to the metabolic adaptation of cells and the organisms. The lysine-specific demethylase-1 (LSD1) is a unique nuclear protein that utilizes flavin adenosine dinucleotide (FAD) as a cofactor. Here we show that LSD1 epigenetically regulates energy-expenditure genes in adipocytes depending on the cellular FAD availability. We find that the loss of LSD1 function, either by short interfering RNA or by selective inhibitors in adipocytes, induces a number of regulators of energy expenditure and mitochondrial metabolism such as PPARγ coactivator-1α resulting in the activation of mitochondrial respiration. In the adipose tissues from mice on a high-fat diet, expression of LSD1-target genes is reduced, compared with that in tissues from mice on a normal diet, which can be reverted by suppressing LSD1 function. Our data suggest a novel mechanism where LSD1 regulates cellular energy balance through coupling with cellular FAD biosynthesis.
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, the Global Center of Excellence 'Cell Fate Regulation Research and Education Unit', Kumamoto University, 860-0811, Japan. s-hino@kumamoto-u.ac.jp
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Hino
authors.forename: Akihisa
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nagaoka
authors.forename: Kotaro
authors.initials: K
authors.lastname: Anan
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Wang
authors.forename: Shinya
authors.initials: S
authors.lastname: Mimasu
authors.forename: Takashi
authors.initials: T
authors.lastname: Umehara
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Kosai
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D059305:Diet, High-Fat; D004435:Eating; D004734:Energy Metabolism; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism*; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D056466:Histone Demethylases; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins
chemical_list: D047495:PPAR gamma; C492635:Phf21a protein, mouse; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D005182:Flavin-Adenine Dinucleotide; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating; D019908:Proto-Oncogene Proteins c-raf; D006655:Histone Deacetylases; D008239:Lysine