The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1β.
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.
Mesh Terms:
3T3-L1 Cells, Animals, Body Weight, Cells, Cultured, Down-Regulation, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Obese, Mitochondria, Obesity, Transcription Factors, Ubiquitin-Protein Ligases, Ubiquitination
3T3-L1 Cells, Animals, Body Weight, Cells, Cultured, Down-Regulation, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Obese, Mitochondria, Obesity, Transcription Factors, Ubiquitin-Protein Ligases, Ubiquitination
EMBO J.
Date: Apr. 15, 2015
PubMed ID: 25698262
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