Phytanic Acid is a Retinoid X Receptor Ligand

Abstract

Metabolic defects in phytanic acid catabolism have been shown to be connected with a number of human diseases which can lead to lethal defects of the nervous system and other organs. These effects are probably a result of the very high accumulation of phytanic acid in tissues throughout the body, due to defects in phytanic acid oxidation, the peroxisome being a major site for this process. The nuclear hormone receptors peroxisome proliferator-activated receptor and retinoid X receptor (RXR) have been shown to function as transcription factors in the control of the peroxisomal enzyme expression. Known activators of peroxisome proliferator-activated receptor include polyunsaturated fatty acids and, for RXR, the 9 4 s isomer of retinoic acid. Here we report that phytanic acid is also a natural ligand for RXRa, being able to activate a RXR-responsive promoter. We present evidence that phytanic acid binds to RXRa, promotes formation of an RXRa/RXR response element complex (as detected by gel retardation), and induces a RXRa conformational change similar to that induced by 9-cis-retinoic acid (as detected by protease sensitivity). These results suggest an involvement of RXRa in the control of fatty acid metabolism and could imply that RXRs have a role in the disease effects resulting from defective phytanic acid catabolism.

Retinoid X receptors: X-ploring their (patho)physiological functions

“…Several molecules have been described as potential endogenous ligands for RXR ( Figure 3): 9-cis RA, 16 phytanic acid 69 and docosahexaenoic acid, 70 but none of these has been proved to be the bona fide endogenous ligand so far. Perlmann and co-workers created a ligand detector mouse line.…”

Activation of Retinold X Receptors by Phytanic acid and Docohexaenoic Acid: Role in the Prevention and Therapy of Prostate Cancer

“…DHA is an essential nutrient for adequate retina and brain development (de Urquiza et al, 2000;Uauy et al, 2001). Both phytanic acid ( (Kitareewan et al, 1996;Lemotte et al, 1996;Radominska-Pandya and Chen, 2002) and DHA are the RXR natural ligands (de Urquiza et al, 2000;Uauy et al, 2001). In this project, we have observed that phytanic acid and DHA, alone and with RAR agonists, suppressed the growth of human prostate cancer cells and decreased the protein level of cyclin D1, a cell cycle regulator.…”

The Potential Role of Binding Proteins in Human Parasitic Infections: An In-Depth Look at the Novel Family of Nematode-Specific Fatty Acid and Retinol Binding Proteins

“…Two other RARinteracting retinoids have been identified in tissue: all-trans 13,14-dihydroretinoic acid and beta -apoands-14'-carotenal [32,33]. Phytanic acid [34], docosahexaenoic acid [35] and other unsaturated fatty acids [36] have been proposed as additional/alternative ligands for RXRs. Future research may investigate the binding abilities FARs to leukotrienes and prostaglandins, both of which are compounds involved in the inflammatory response [18].…”