The peroxisome proliferator-activated receptor δ, an integrator of transcriptional repression and nuclear receptor signaling

The three PPAR (peroxisome proliferator-activated receptor) isoforms are critical regulators of lipid homeostasis by controlling the balance between the burning and storage of long chain fatty acids. Whereas PPARalpha and PPARgamma have been studied extensively, the function of PPARdelta remains the most elusive. Intriguingly, in cotransfection experiments, PPARdelta is a potent inhibitor of ligand-induced transcriptional activity of PPARalpha and PPARgamma. This inhibition is achieved, in part, by binding of PPARdelta to a peroxisome proliferator response element and the association of nonliganded PPARdelta with corepressors SMRT (silencing mediator for retinoid and thyroid hormone receptors), SHARP (SMRT and histone deacetylase-associated repressor protein), and class I histone deacetylases. Stable expression of PPARdelta inhibits the expression of endogenous PPARalpha target gene expression in 3T3-PPARalpha cells, whereas a PPARdelta mutant that does not interact with the corepressor SMRT loses its ability to repress the induction of PPARalpha target gene. Similarly, stable expression of PPARdelta in 3T3-PPARgamma cells leads to inhibition of PPARgamma target gene expression and PPARgamma-mediated adipogenesis. Given the widespread expression of PPARdelta and the restricted pattern for PPARalpha and PPARgamma, these results suggest a role for PPARdelta as a gateway receptor whose relative levels of expression can be used to modulate PPARalpha and PPARgamma activity.