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- Title
Pioglitazone Increases SUMOylation in Human Adipose Tissue.
- Authors
Bodles, Angela; Varma, Vijayalakshmi; Yao-Borengasser, Aiwei; Phanavanh, Bounleut; Rashidi, Amir Adel; Mcgehee, Robert; Rasouli, Neda; Kern, Philip
- Abstract
PPARγplays a major role in cell differentiation, lipid metabolism and apoptosis and is the target of thiazolidinediones which are widely used to improve insulin sensitivity and for treatment of diabetes mellitus. Recently a SUMOylation (small ubiquitin-like modifier) site was identified on PPARγsuggesting that it might be a target for modification by SUMO-1. SUMOylation, a process similar to ubiquitination, regulates many cellular processes including nuclear transport, transcription, apuptosis and protein stability. SUMOylation of PPARγhas been proposed to play a role in the transrepression of inflammatory genes. We hypothesized that pioglitazone (pin) would increase the amount of PPARγmodified by SUMO-1, and that this could be part of the anti-inflammatory effect of TZDs. To evaluate SUMOylation we examined human adipose tissue mRNA levels for SUMO-1 in 18 impaired glucose tolerant subjects in response to two insulin-sensitizing drugs (pin and metfromin). We found that pin treatment increased expression of SUMO-1 by 23% (p<0.002). When added to adipocytes in vitro, pin also increased SUMO-1 suggesting a direct effect of TZDs on adipocytes. Next, we examined the expression of SUMO-1 and NCOR (nuclear receptor corepressor protein) in adipose tissue from 86 subjects (54 NGT and 32 IGT) covering a broad range of BMI and S[sub 1]. SUMO-1 and NCOR correlated strongly with each other (r=0.8, p<0.001) suggesting that they are tightly associated in a large complex as described previously in cultured macrophages where SUMOylation of PPARγ promotes interaction with the NCOR-histone deacetylase3 complex and represses target genes. Although SUMO-1 and NCOR were not significantly associated with BMI or S[sub 1] in this group, they were highly associated with inflammatory markers. Adipose CD68 and MCP1 mRNA levels correlated strongly with SUMO-1 and NCOR (r=0.5 and 0.6, p<0.001 respectively). Overall these results show that SUMOylation of PPARγcan be regulated by pin treatment and suggest that the anti-inflammatory effects of pio may be controlled by the degree of SUMO-1 modification of PPARγ.
- Subjects
HYPOGLYCEMIC agents; UBIQUITIN; ADIPOSE tissues; LIPID metabolism; APOPTOSIS; CELL differentiation; TREATMENT of diabetes; MESSENGER RNA
- Publication
Diabetes, 2007, Vol 56, pA360
- ISSN
0012-1797
- Publication type
Article