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

Fujita, Hidetoshi; Yagishita, Naoko; Aratani, Satoko; Saito-Fujita, Tomoko; Morota, Saori; Yamano, Yoshihisa; Hansson, Magnus LU ; Inazu, Masato; Kokuba, Hiroko and Sudo, Katsuko, et al. (2015) In EMBO Journal 34(8). p.1042-1055
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)-1 beta, and Syvn1 mutants showed upregulation of PGC-1 beta... (More)
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)-1 beta, and Syvn1 mutants showed upregulation of PGC-1 beta 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-1 beta by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1 beta and a potential therapeutic target in obesity treatment. (Less)
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Contribution to journal
publication status
published
subject
keywords
endoplasmic reticulum, mitochondria, obesity, PGC-1 beta, synoviolin
in
EMBO Journal
volume
34
issue
8
pages
1042 - 1055
publisher
Oxford University Press
external identifiers
  • wos:000352997000008
ISSN
1460-2075
language
English
LU publication?
yes
id
da1f28ab-c6d8-4ebe-bda4-26f69f2430a4 (old id 5395206)
date added to LUP
2015-06-01 09:25:25
date last changed
2016-08-26 16:08:56
@article{da1f28ab-c6d8-4ebe-bda4-26f69f2430a4,
  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)-1 beta, and Syvn1 mutants showed upregulation of PGC-1 beta 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-1 beta by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1 beta and a potential therapeutic target in obesity treatment.},
  author       = {Fujita, Hidetoshi and Yagishita, Naoko and Aratani, Satoko and Saito-Fujita, Tomoko and Morota, Saori and Yamano, Yoshihisa and Hansson, Magnus and Inazu, Masato and Kokuba, Hiroko and Sudo, Katsuko and Sato, Eiichi and Kawahara, Ko-ichi and Nakajima, Fukami and Hasegawa, Daisuke and Higuchi, Itsuro and Sato, Tomoo and Araya, Natsumi and Usui, Chie and Nishioka, Kenya and Nakatani, Yu and Maruyama, Ikuro and Usui, Masahiko and Hara, Naomi and Uchino, Hiroyuki and Elmer, Eskil and Nishioka, Kusuki and Nakajima, Toshihiro},
  issn         = {1460-2075},
  keyword      = {endoplasmic reticulum,mitochondria,obesity,PGC-1 beta,synoviolin},
  language     = {eng},
  number       = {8},
  pages        = {1042--1055},
  publisher    = {Oxford University Press},
  series       = {EMBO Journal},
  title        = {The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1 beta},
  volume       = {34},
  year         = {2015},
}