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The E3 ligase synoviolin controls body weight and mitochondrial biogenesis
through negative regulation of PGC-1?
#MMPMID25698262
Fujita H
; Yagishita N
; Aratani S
; Saito-Fujita T
; Morota S
; Yamano Y
; Hansson MJ
; Inazu M
; Kokuba H
; Sudo K
; Sato E
; Kawahara K
; Nakajima F
; Hasegawa D
; Higuchi I
; Sato T
; Araya N
; Usui C
; Nishioka K
; Nakatani Y
; Maruyama I
; Usui M
; Hara N
; Uchino H
; Elmer E
; Nishioka K
; Nakajima T
EMBO J
2015[Apr]; 34
(8
): 1042-55
PMID25698262
show ga
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?, and Syvn1 mutants showed
upregulation of PGC-1? 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? by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a
novel post-translational regulator of PGC-1? and a potential therapeutic target
in obesity treatment.
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