Subtype- and response element-dependent differences in transactivation by peroxisome proliferator-activated receptors α and γ

Abstract

Peroxisome proliferator-activated receptors (PPAR) modulate transcription by binding to specific peroxisome proliferator-response elements (PPRE) through heterodimerization with the 9- cis retinoic acid receptor (RXR). To investigate potential subtype- and response element-dependent differences in transcriptional activation by PPARs, we expressed PPAR α or PPAR γ2, along with RXR α, in the yeast Saccharoromyces cerevisiae and compared their ability to activate transcription of reporter genes containing a PPRE from either the rat acyl-CoA oxidase (AOx) or hydratase-dehydrogenase (HD) gene. PPAR γ2 and RXR α, when coexpressed from low copy vectors, potently and synergistically activated transcription of the AOx-PPRE reporter gene, but only weakly stimulated transcription of the HD-PPRE reporter gene. This response element preference, which was also observed in mammalian cells, could not be attributed to differences in binding affinity of PPAR γ2/RXR α heterodimers to these elements in vitro. Interestingly, PPAR γ2 expressed from a high copy vector was able to strongly activate transcription of the HD-PPRE reporter gene, even in the absence of coexpressed RXR α. In comparison to the findings with PPAR γ2, the HD-PPRE served as a significantly more robust response element for PPAR α as compared to the AOx-PPRE. PPRE-dependent transcriptional activation by PPAR α correlated with binding efficiencies of PPAR α/RXR α to the response element. Our findings demonstrate that the transactivation potential of PPAR subtypes can be differentially modulated by distinct PPREs.