Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR

Mol Biol Cell. 1996 Aug;7(8):1153-66. doi: 10.1091/mbc.7.8.1153.

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.

MeSH terms

  • Animals
  • CHO Cells
  • Cattle
  • Cricetinae
  • Dietary Fats / metabolism
  • Fatty Acids, Essential / isolation & purification
  • Fatty Acids, Essential / metabolism
  • In Vitro Techniques
  • Ligands
  • Phytanic Acid / analogs & derivatives
  • Phytanic Acid / isolation & purification
  • Phytanic Acid / metabolism
  • Phytanic Acid / pharmacology
  • Phytol / metabolism*
  • Receptors, Retinoic Acid / drug effects
  • Receptors, Retinoic Acid / metabolism*
  • Refsum Disease / metabolism
  • Retinoid X Receptors
  • Signal Transduction
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism*
  • Tretinoin / blood
  • Tretinoin / metabolism

Substances

  • Dietary Fats
  • Fatty Acids, Essential
  • Ligands
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factors
  • Phytanic Acid
  • Phytol
  • phytenic acid
  • Tretinoin