Premium
The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC ‐1β
Author(s) -
Fujita Hidetoshi,
Yagishita Naoko,
Aratani Satoko,
SaitoFujita Tomoko,
Morota Saori,
Yamano Yoshihisa,
Hansson Magnus J,
Inazu Masato,
Kokuba Hiroko,
Sudo Katsuko,
Sato Eiichi,
Kawahara Koichi,
Nakajima Fukami,
Hasegawa Daisuke,
Higuchi Itsuro,
Sato Tomoo,
Araya Natsumi,
Usui Chie,
Nishioka Kenya,
Nakatani Yu,
Maruyama Ikuro,
Usui Masahiko,
Hara Naomi,
Uchino Hiroyuki,
Elmer Eskil,
Nishioka Kusuki,
Nakajima Toshihiro
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201489897
Subject(s) - biology , ubiquitin ligase , mitochondrial biogenesis , biogenesis , mitochondrion , microbiology and biotechnology , genetics , gene , ubiquitin
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. SYVN 1 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 SYVN 1 inhibitor LS ‐102 abolished the negative regulation of PGC ‐1β by SYVN 1 and prevented weight gain in mice. Thus, SYVN 1 is a novel post‐translational regulator of PGC ‐1β and a potential therapeutic target in obesity treatment.