The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC ‐1β

Autor: Hiroyuki Uchino, Kusuki Nishioka, Kenya Nishioka, Yu Nakatani, Daisuke Hasegawa, Ko-ichi Kawahara, Naomi Hara, Eskil Elmér, Naoko Yagishita, Hiroko Kokuba, Fukami Nakajima, Tomoko Saito-Fujita, Satoko Aratani, Toshihiro Nakajima, Tomoo Sato, Saori Morota, Magnus Hansson, Itsuro Higuchi, Katsuko Sudo, Eiichi Sato, Hidetoshi Fujita, Masahiko Usui, Natsumi Araya, Chie Usui, Yoshihisa Yamano, Masato Inazu, Ikuro Maruyama
Rok vydání: 2015
Předmět:
Zdroj: The EMBO Journal. 34:1042-1055
ISSN: 1460-2075
0261-4189
DOI: 10.15252/embj.201489897
Popis: 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.
Databáze: OpenAIRE
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