title: Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR.
abstract: 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 by following RXR-dependent transcriptional activity. Structural analyses of material in active fractions pointed to the saturated diterpenoid phytanic acid, which induced RXR-dependent transcription at concentrations between 4 and 64 microM. Although 200 times more potent than phytanic acid, 9cRA was undetectable in equivalent amounts of extract and cannot be present at a concentration that could account for the activity. Phytanic acid, another phytol metabolite, was synthesized and stimulated RXR with a potency and efficacy similar to phytanic acid. These metabolites specifically displaced [3H]-9cRA from RXR with Ki values of 4 microM, indicating that their transcriptional effects are mediated by direct receptor interactions. Phytol metabolites are compelling candidates for physiological effectors, because their RXR binding affinities and activation potencies match their micromolar circulating concentrations. Given their exclusive dietary origin, these chlorophyll metabolites may represent essential nutrients that coordinate cellular metabolism through RXR-dependent signaling pathways.
authors.affiliation: Orphan Receptor Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kitareewan
authors.forename: L T
authors.initials: LT
authors.lastname: Burka
authors.forename: K B
authors.initials: KB
authors.lastname: Tomer
authors.forename: C E
authors.initials: CE
authors.lastname: Parker
authors.forename: L J
authors.initials: LJ
authors.lastname: Deterding
authors.forename: R D
authors.initials: RD
authors.lastname: Stevens
authors.forename: B M
authors.initials: BM
authors.lastname: Forman
authors.forename: D E
authors.initials: DE
authors.lastname: Mais
authors.forename: R A
authors.initials: RA
authors.lastname: Heyman
authors.forename: T
authors.initials: T
authors.lastname: McMorris
authors.forename: C
authors.initials: C
authors.lastname: Weinberger
mesh_terms: D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D004041:Dietary Fats / Q000378:metabolism; D005228:Fatty Acids, Essential / Q000302:isolation & purification / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D010831:Phytanic Acid / Q000031:analogs & derivatives / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D010836:Phytol / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism*; D012035:Refsum Disease / Q000378:metabolism; D047488:Retinoid X Receptors; D015398:Signal Transduction; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014212:Tretinoin / Q000097:blood / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D005228:Fatty Acids, Essential; D008024:Ligands; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D010831:Phytanic Acid; D010836:Phytol; C045824:phytenic acid; D014212:Tretinoin