of Work: RXR is a nuclear receptor which plays a central role in cell signalling by pairing with a host of other receptors. Previously, all-trans-retinoic acid and 9-cis-retinoic acid were characterized as RXR effectors. In contrast, we have identified phytenic acid and phytanic acid as circulating branched chain fatty acids from chloroform extracts of bovine serum by following RXR-dependent transcriptional activity. Mass spectrometric analyses of material in active fractions pointed to these saturated diterpenoid acids, which induced RXR-dependent activity at concentrations between 4 and 64 uM. 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. Phytenic 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 uM, 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 amounts. Given their exclusive dietary origin, these chlorophyll metabolites may represent essential nutrients that coordinate cellular metabolism through RXR-dependent signalling pathways. This hypothesis is being tested by comparing the growth of mice and rats raised on phytanic acid-deficient diets with groups of animals fed diets supplemented with phytanic acid. In summary, these findings lead us to propose that phytol metabolites may be nutritional signals linking the animal's dietary state with a variety of endocrine and intracrine signalling pathways through the nuclear receptor RXR.
