Ligand Modulated Antagonism Of Ppar Gamma By Genomic And Non-Genomic Actions Of Ppar Delta

Background: Members of the Peroxisome Proliferator Activated Receptor, PPAR, subfamily of nuclear receptors display complex opposing and overlapping functions and a wide range of pharmacological and molecular genetic tools have been used to dissect their specific functions. Non-agonist bound PPAR delta has been shown to repress PPAR Response Element, PPRE, signalling and several lines of evidence point to the importance of PPAR delta repressive actions in both cardiovascular and cancer biology.Methodology/Principal Findings: In this report we have employed transient transfections and luciferase reporter gene technology to study the repressing effects of PPAR delta and two derivatives thereof. We demonstrate for the first time that the classical dominant negative deletion of the Activation Function 2, AF2, domain of PPAR delta show enhanced repression of PPRE signalling in the presence of a PPAR delta agonist. We propose that the mechanism for the phenomenon is increased RXR heterodimerisation and DNA binding upon ligand binding concomitant with transcriptional co-repressor binding. We also demonstrated ligand-dependent dominant negative action of a DNA non-binding derivative of PPAR delta on PPAR gamma 1 signalling. This activity was abolished upon over-expression of RXR alpha suggesting a role for PPAR/cofactor competition in the absence of DNA binding.Conclusions/Significance: These findings are important in understanding the wide spectrum of molecular interactions in which PPAR delta and PPAR gamma have opposing biological roles and suggest novel paradigms for the design of different functional classes of nuclear receptor antagonist drugs.