Conditional Expression of Human PPARδand a Dominant Negative Variant of hPPARδ In Vivo

The nuclear receptor, NR1C2 or peroxisome proliferator-activated receptor (PPAR)- δ , is ubiquitously expressed and important for placental development, fatty acid metabolism, wound healing, inflammation, and tumour development. PPAR δ has been hypothesized to function as both a ligand activated transcription factor and a repressor of transcription in the absence of agonist. In this paper, treatment of mice conditionally expressing human PPAR δ with GW501516 resulted in a marked loss in body weight that was not evident in nontransgenic animals or animals expressing a dominant negative derivative of PPAR δ . Expression of either functional or dominant negative hPPAR δ blocked bezafibrate-induced PPAR α -dependent hepatomegaly and blocked the effect of bezafibrate on the transcription of PPAR α target genes. These data demonstrate, for the first time, that PPAR δ could inhibit the activation of PPAR α in vivo and provide novel models for the investigation of the role of PPAR δ in pathophysiology.