Received for publication July 16, 2008.
Revised August 11, 2008.
Accepted for publication August 13, 2008.

Ligand-mediated regulation of PPAR/: a comparative analysis of PPAR-selective agonists and all-trans retinoic acid (atRA)

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. Intriguingly, all trans-retinoic acid (atRA) has recently been reported to act as a ligand for PPAR/, to activate its transcriptional activity and, in contrast to the "classical" function of atRA, to stimulate cell proliferation (Schug et al., 2007). Here, we report that in contrast to synthetic PPAR/ agonists, atRA failed to induce the transcriptional activity of / using different types of reporter gene assays. Similarly, atRA did not affect the expression of the bona fide PPAR/ 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 PPAR/ agonists in a ligand binding assay, and atRA did not enable the interaction of PPAR/ with a co-activator peptide in a time resolved fluorescence resonance energy transfer assay in vitro. These results are in sharp contrast to the effect of established PPAR/ agonists in both in vitro assays. Collectively, these data strongly suggest that atRA does not function as a ligand of PPAR/ 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.

Key words: PPARs, Transcriptional coactivators, DNA binding sites, Promoter analysis

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