Retinoic Acid Is a High Affinity Selective Ligand for the Peroxisome Proliferator-activated Receptor β/δ

Abstract

Retinoic acid (RA) modulates transcription of numerous target genes, thereby regulating a myriad of biological processes. It is well established that RA functions by activating retinoic acid receptors (RARs), which, in turn, control cell differentiation, proliferation, and apoptosis. However, perplexing reports of diverse and sometime opposing actions of RA have been published. Hence, while RA induces apoptosis and inhibits cell growth in some settings, it potentiates proliferation and acts as an anti-apoptotic agent in others. These observations raise the possibility that signaling pathways other than RAR may be involved in mediating RA activities. Here we show that RA is a high affinity ligand for another nuclear receptor, namely the orphan receptor peroxisome proliferator-activated receptor (PPAR) ␤/␦. We demonstrate that while RA does not activate PPAR␣ and PPAR␥, it binds to PPAR␤/␦ with nanomolar affinity, modulates the conformation of the receptor, promotes interaction with the coactivator SRC-1, and efficiently activates PPAR␤/␦-mediated transcription. Transcriptional signaling by RA is thus exerted by a dual pathway, providing a rationale for understanding divergent cellular responses to this hormone.

HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues

“…Specific binding proteins, enzymes, and receptors control flux through the central pathways of retinoid homeostasis, ultimately to produce retinoic acid, an active form of vitamin A (Figure 1) (6)(7). RA effects a wide range of physiological processes, including development, nervous system function, immune response, cell proliferation, cell differentiation, and reproduction through activation of type II nuclear receptors (RAR, RXR, PPARβ/δ) (8)(9)(10)(11)(12)(13)(14)(15). RA exerts additional biological effects through dimerization of RXR with an array of other type II nuclear receptors (13).…”

Effects of dietary retinoids and carotenoids on immune development

“…These effects have been shown to be mediated via the PPARb-(also known as PPARd) RXR receptor heterodimer during wound healing (Tan et al 2001(Tan et al , 2003Di-Poi et al 2002). PPARb/d-mediated transcription may be activated via: (a) PPARb/d agonists (for review, see Tan et al 2005); (b) RXR agonists such as 9-cis-retinoic acid (Tan et al 2005); (c) all-trans-retinoic acid (Shaw et al 2003).…”

Cellular Retinoic Acid-binding Protein 2 Inhibits Tumor Growth by Two Distinct Mechanisms

“…The vitamin A metabolite retinoic acid (RA) 3 regulates gene transcription by activating several members of the nuclear receptor family of transcription factors: the classical RA receptors (RARs) (1,2) and peroxisome proliferator-activated receptor ␤/␦ (PPAR␤/␦) (3,4). The partitioning of RA between these receptors is regulated by two intracellular lipid-binding proteins: cellular retinoic acid-binding protein 2 (CRABP2), which has a high affinity for the hormone and shuttles it to RARs, and fatty acid-binding protein 5 (FABP5), which has a lower affinity for RA and delivers it to PPAR␤/␦.…”