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

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 alpha or PPAR gamma 2, along with RXR alpha, 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 gamma 2 and RXR alpha, 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 gamma 2/RXR alpha heterodimers to these elements in vitro. Interestingly, PPAR gamma 2 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 alpha. In comparison to the findings with PPAR gamma 2, the HD-PPRE served as a significantly more robust response element for PPAR alpha as compared to the AOx-PPRE. PPRE-dependent transcriptional activation by PPAR alpha correlated with binding efficiencies of PPAR alpha/RXR alpha to the response element. Our findings demonstrate that the transactivation potential of PPAR subtypes can be differentially modulated by distinct PPREs. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.