title: The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1β.
abstract: Obesity is a major global public health problem, and understanding its pathogenesis is critical for identifying a cure. In this study, a gene knockout strategy was used in post-neonatal mice to delete synoviolin (Syvn)1/Hrd1/Der3, an ER-resident E3 ubiquitin ligase with known roles in homeostasis maintenance. Syvn1 deficiency resulted in weight loss and lower accumulation of white adipose tissue in otherwise wild-type animals as well as in genetically obese (ob/ob and db/db) and adipose tissue-specific knockout mice as compared to control animals. SYVN1 interacted with and ubiquitinated the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1β, and Syvn1 mutants showed upregulation of PGC-1β target genes and increase in mitochondrion number, respiration, and basal energy expenditure in adipose tissue relative to control animals. Moreover, the selective SYVN1 inhibitor LS-102 abolished the negative regulation of PGC-1β by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1β and a potential therapeutic target in obesity treatment.
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan Department of Future Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Yagishita
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan Department of Future Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Aratani
authors.affiliation: Department of Obstetrics and Gynecology University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Saito-Fujita
authors.affiliation: Department of Anesthesiology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Morota
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamano
authors.affiliation: Mitochondrial Pathophysiology Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Hansson
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Inazu
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kokuba
authors.affiliation: Animal Research Center, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Katsuko
authors.initials: K
authors.lastname: Sudo
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan Medical Research Center, Tokyo Medical University Hospital, Shinjuku-ku, Tokyo, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sato
authors.affiliation: Department of Biomedical Engineering, Osaka Institute of Technology, Asahi-ku, 11Neurology and Geriatrics, Japan.
authors.forename: Ko-Ichi
authors.initials: K
authors.lastname: Kawahara
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Fukami
authors.initials: F
authors.lastname: Nakajima
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hasegawa
authors.affiliation: Neurology and Geriatrics, Faculty of Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan.
authors.forename: Itsuro
authors.initials: I
authors.lastname: Higuchi
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Sato
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Araya
authors.affiliation: Department of Psychiatry, Juntendo University Nerima Hospital, Nerima-ku, Tokyo, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Usui
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Nishioka
authors.affiliation: Department of Future Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Nakatani
authors.affiliation: Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan.
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Usui
authors.affiliation: Department of Anesthesiology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Hara
authors.affiliation: Department of Anesthesiology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchino
authors.affiliation: Mitochondrial Pathophysiology Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Eskil
authors.initials: E
authors.lastname: Elmer
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kusuki
authors.initials: K
authors.lastname: Nishioka
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan Department of Future Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan Medical Research Center, Tokyo Medical University Hospital, Shinjuku-ku, Tokyo, Japan Department of Biomedical Engineering, Osaka Institute of Technology, Asahi-ku, 11Neurology and Geriatrics, Japan integrated Gene Editing Section (iGES), Tokyo Medical University Hospital, Shinjuku-ku, Tokyo, Japan Bayside Misato Medical Center, Niida, Kōchi, Japan marlin@tokyo-med.ac.jp.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001835:Body Weight / Q000235:genetics*; D002478:Cells, Cultured; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008928:Mitochondria / Q000502:physiology*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D054875:Ubiquitination / Q000235:genetics
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: PGC‐1β; endoplasmic reticulum; mitochondria; obesity; synoviolin