Objective-Drugs that activate peroxisome proliferator-activated receptor (PPAR) γ improve glucose sensitivity and lower blood pressure, whereas dominant-negative mutations in PPARγ cause severe insulin resistance and hypertension. We hypothesize that these PPARγ mutants regulate target genes opposite to those of ligand-mediated activation, and we tested this hypothesis on a genomewide scale. Methods and Results-We integrated gene expression data in aorta specimens from mice treated with the PPARγ ligand rosiglitazone with data from mice containing a globally expressed knockin of the PPARγ P465L dominant-negative mutation. We also integrated our data with publicly available data sets containing the following: (1) gene expression profiles in many human tissues, (2) PPARγ target genes in 3T3-L1 adipocytes, and (3) experimentally validated PPARγ binding sites throughout the genome. Many classic PPARγ target genes were induced by rosiglitazone and repressed by dominant-negative PPARγ. A similar pattern was observed for about 90% of the gene sets regulated by both rosiglitazone and dominant-negative PPARγ. Genes exhibiting this pattern of contrasting regulation were significantly enriched for nearby PPARγ binding sites. Conclusion-These results provide convincing evidence that the PPARγ P465L mutation causes transcriptional effects that are opposite to those mediated by PPARγ ligand, thus validating mice carrying the mutation as a model of PPARγ interference.
|Number of pages||8|
|Journal||Arteriosclerosis, thrombosis, and vascular biology|
|State||Published - Mar 2010|
- PPARγ microarray
- Transcription factor