Non-classical Transcriptional Activity of Retinoic Acid

It has long been established that the transcriptional activity of retinoic acid (RA) is mediated by members of the nuclear receptor family of ligand-activated transcription factors termed RA receptors (RARs). More recent observations have established that RA also activates an additional nuclear receptor, PPARβ/δ. Partitioning RA between RARs and PPARβ/δ is governed by different intracellular lipid-binding proteins: cellular RA binding protein 2 (CRABP2) delivers RA to nuclear RARs and a fatty acid binding protein (FABP5) delivers the hormone from the cytosol to nuclear PPARβ/δ. Consequently, RA signals through RARs in CRABP2-expressing cells, but activates PPARβ/δ in cells that express a high level of FABP5. RA elicits different and sometimes opposing responses in cells that express different FABP5/CRABP2 ratios because PPARβ/δ and RARs regulate the expression of distinct sets of genes. An overview of the observations that led to the discovery of this non-classical activity of RA are presented here, along with a discussion of evidence demonstrating the involvement of the dual transcriptional activities of RA in regulating energy homeostasis, insulin responses, and adipocyte and neuron differentiation.