The ubiquitin ligase Siah2 regulates PPAR? activity in adipocytes.

ABSTRACT: Moderate reductions in peroxisome proliferator-activated receptor (PPAR)? levels control insulin sensitivity as effectively as activation of PPAR? in adipocytes by the thiazolidinediones. That observation suggests that PPAR? activity can be regulated by modulating the amount of PPAR? protein in adipocytes. Activation of PPAR? in adipocytes is linked to changes in PPAR? protein levels via increased degradation of PPAR? proteins by the ubiquitin proteasome system. Identification of the ubiquitin ligase or ligases that recognize ligand bound PPAR? is an essential step in determining the physiological significance of the relationship between activation and ubiquitin-dependent degradation of PPAR?. Using an RNA interference-based screen, we identified five RING (really interesting new gene)-type ubiquitin ligases that alter PPAR? protein levels in adipocytes. Here, we demonstrate that Drosophila seven-in-absentia homolog 2 (Siah2), a mammalian homolog of Drosophila seven-in-absentia, regulates PPAR? ubiquitylation and ligand-dependent activation of PPAR? in adipocytes. We also demonstrate that Siah2 expression is up-regulated during adipogenesis and that PPAR? interacts with Siah2 during adipogenesis. In addition, Siah2 is required for adipogenesis. These data suggest that modulation of PPAR? protein levels by the ubiquitin ligase Siah2 is essential in determining the physiological effects of PPAR? activation in adipocytes.

SUBMITTER: Kilroy G 

PROVIDER: S-EPMC3281538 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature