Is PPARβ/δa Retinoid Receptor?

The broad ligand-binding characteristic of PPARβ/δ has long hampered identification of physiologically-meaningful ligands for the receptor. The observations that the activity of PPARβ/δ is supported by fatty acid binding protein 5 (FABP5), which directly delivers ligands from the cytosol to the receptor, suggest that bona fide PPARβ/δ ligands both activate the receptor, and trigger the nuclear translocation of FABP5. Using these criteria, it was recently demonstrated that all-trans-retinoic acid (RA), the activator of the classical retinoic acid receptor RAR, also serves as a ligand for PPARβ/δ. Partitioning of RA between its two receptors was found to be regulated by FABP5, which delivers it to PPARβ/δ, and cellular RA binding protein II (CRABP-II), which targets it to RAR. Consequently, RA activates PPARβ/δ in cells that display a high FABP5/CRABP-II expression ratio. It remains to be clarified whether compounds other than RA may also serve as endogenous activators for this highly promiscuous protein.