Non-classical Transcriptional Activity of Retinoic Acid.

ABSTRACT

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, PPARß/δ. Partitioning RA between RARs and PPARß/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 PPARß/δ. Consequently, RA signals through RARs in CRABP2-expressing cells, but activates PPARß/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 PPARß/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.