Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that modulate target gene expression in response to natural fatty acid ligands and synthetic agonists. It is noteworthy that all trans-retinoic acid (atRA) has recently been reported to act as a ligand for PPARβ/δ, to activate its transcriptional activity, and, in contrast to the “classic” function of atRA, to stimulate cell proliferation (Schug et al., 2007). Here, we report that in contrast to synthetic PPARβ/δ agonists, atRA failed to induce the transcriptional activity of PPARβ/δ using different types of reporter gene assays. Likewise, atRA did not affect the expression of the bona fide PPARβ/δ target genes ADRP and ANGPTL4 but strongly increased expression of the retinoic acid target gene CYP26A under the identical experimental conditions. Consistent with these observations, atRA did not compete with established PPARβ/δ agonists in a ligand binding assay, and atRA did not enable the interaction of PPARβ/δ with a coactivator peptide in a time-resolved fluorescence resonance energy transfer assay in vitro. These results are in sharp contrast to the effect of established PPARβ/δ agonists in both in vitro assays. Taken as a whole, these data strongly suggest that atRA does not function as a ligand of PPARβ/δ in any of the experimental systems tested and that the previously reported atRA effects are more likely to reflect an uncharacterized and less direct mechanism.