Dataset Information

Troglitazone induces cytotoxicity in part by promoting the degradation of peroxisome proliferator-activated receptor γ co-activator-1α protein.

ABSTRACT:

Background and purpose

Troglitazone (Tro), rosiglitazone (Rosi) and pioglitazone (Pio) are anti-diabetic thiazolidinediones that function as ligands for peroxisome proliferator-activated receptor γ (PPARγ); however, Tro has been withdrawn from the market due to liver toxicity issues. Mitochondrial dysfunction induced by Tro has been suggested to be an important mechanism behind its cytotoxicity. Constitutively active nuclear hormone receptors, oestrogen-related receptor α and γ are thought to regulate mitochondrial mass and oxidative phosphorylation together with their co-activators PPARγ co-activator-1α and -1β (PGC-1α and PGC-1β). Hence, in this study, we investigated whether Tro affects the expression and activity levels of these regulators.

Experimental approach

Cellular viability was measured by an ATP-based assay. Mitochondrial mass and reactive oxygen species (ROS) were quantified by two different fluorogenic probes. Apoptosis was measured by an Annexin-V-based kit. Gene expression at the levels of mRNA and protein was measured by quantitative RT-PCR and Western analysis. Over-expression of PGC-1α was mediated by an adenovirus.

Key results

Tro, but not Rosi or Pio, selectively stimulated PGC-1α protein degradation. As a result, Tro reduced mitochondrial mass, and superoxide dismutases 1 and 2 expressions, but induced ROS to initiate apoptosis. Using a ubiquitin-proteasome inhibitor MG132, it was established that blocking PGC-1α degradation partially suppressed the reduction of mitochondrial mass. Importantly, over-expressing PGC-1α partially restored the Tro-suppressed mitochondrial mass and attenuated the cytotoxic effects of Tro.

Conclusions and implications

Collectively, these results suggest that PGC-1α degradation is an important mechanism behind the cytotoxic effects of Tro in the liver.

SUBMITTER: Liao X

PROVIDER: S-EPMC2992894 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Publications

Troglitazone induces cytotoxicity in part by promoting the degradation of peroxisome proliferator-activated receptor γ co-activator-1α protein.

Liao Xuemei X Wang Yanfei Y Wong Chi-Wai CW

British journal of pharmacology 20101001 4

<h4>Background and purpose</h4>Troglitazone (Tro), rosiglitazone (Rosi) and pioglitazone (Pio) are anti-diabetic thiazolidinediones that function as ligands for peroxisome proliferator-activated receptor γ (PPARγ); however, Tro has been withdrawn from the market due to liver toxicity issues. Mitochondrial dysfunction induced by Tro has been suggested to be an important mechanism behind its cytotoxicity. Constitutively active nuclear hormone receptors, oestrogen-related receptor α and γ are thoug ...[more]

PMID: 20860658

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Dataset Information

Troglitazone induces cytotoxicity in part by promoting the degradation of peroxisome proliferator-activated receptor γ co-activator-1α protein.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Troglitazone induces cytotoxicity in part by promoting the degradation of peroxisome proliferator-activated receptor γ co-activator-1α protein.

Similar Datasets

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