PHYTOL METABOLITES ARE CIRCULATING DIETARY FACTORS THAT ACTIVATE THE NUCLEAR RECEPTOR RXR

RXR is a nuclear receptor that plays a central role in cell signaling by pairing with a host of other receptors. Previously, 9-cis-retinoic acid (9cRA) was defined as a potent RXR activator. Here we describe a unique RXR effector identified from organic extracts of bovine serum b y following RXR-dependent transcriptional activity. Structural analyse s of material in active fractions pointed to the saturated diterpenoid phytanic acid, which induced RXR-dependent transcription at concentra tions between 4 and 64 mu M. Although 200 times more potent than phyta nic acid, 9cRA was undetectable in equivalent amounts of extract and c annot be present at a concentration that could account for the activit y. Phytenic acid, another phytol metabolite, was synthesized and stimu lated RXR with a potency and efficacy similar to phytanic acid. These metabolites specifically displaced [H-3]-9cRA from RXR with K-i values of 4 mu M, indicating that their transcriptional effects are mediated by direct receptor interactions. Phytol metabolites are compelling ca ndidates for physiological effecters, because their RXR binding affini ties and activation potencies match their micromolar circulating conce ntrations. Given their exclusive dietary origin, these chlorophyll met abolites may represent essential nutrients that coordinate cellular me tabolism through RXR-dependent signaling pathways.