Bioinformatic analysis of gene sets regulated by ligand-activated and dominant-negative peroxisome proliferator-activated receptor gamma in mouse aorta.

Abstract

OBJECTIVE:

Drugs that activate peroxisome proliferator-activated receptor (PPAR) gamma improve glucose sensitivity and lower blood pressure, whereas dominant-negative mutations in PPARgamma cause severe insulin resistance and hypertension. We hypothesize that these PPARgamma 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 PPARgamma ligand rosiglitazone with data from mice containing a globally expressed knockin of the PPARgamma 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) PPARgamma target genes in 3T3-L1 adipocytes, and (3) experimentally validated PPARgamma binding sites throughout the genome. Many classic PPARgamma target genes were induced by rosiglitazone and repressed by dominant-negative PPARgamma. A similar pattern was observed for about 90% of the gene sets regulated by both rosiglitazone and dominant-negative PPARgamma. Genes exhibiting this pattern of contrasting regulation were significantly enriched for nearby PPARgamma binding sites.

CONCLUSIONS:

These results provide convincing evidence that the PPARgamma P465L mutation causes transcriptional effects that are opposite to those mediated by PPARgamma ligand, thus validating mice carrying the mutation as a model of PPARgamma interference.

• Authors: Henry L Keen, Carmen M Halabi, Andreas M Beyer, Willem J de Lange, Xuebo Liu, Nobuyo Maeda, Frank M Faraci, Thomas L Casavant, Curt D Sigmund
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 3 Pg. 518-25 (Mar 2010) ISSN: 1524-4636 [Electronic] United States
• PMID: 20018933 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• PPAR gamma
• Thiazolidinediones
• Rosiglitazone

Topics

• Animals
• Aorta, Thoracic (metabolism)
• Computational Biology
• Gene Expression Profiling
• Ligands
• Mice
• Mice, Inbred C57BL
• Models, Animal
• Mutation
• PPAR gamma (genetics, metabolism)
• Rosiglitazone
• Signal Transduction (physiology)
• Thiazolidinediones (pharmacology)
• Up-Regulation (drug effects)