Phytanic acid is a retinoid X receptor ligand.
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-cis isomer of retinoic acid. Here we report that phytanic acid is also a natural ligand for RXR alpha, being able to activate a RXR-responsive promoter. We present evidence that phytanic acid binds to RXR alpha, promotes formation of an RXR alpha/RXR response element complex (as detected by gel retardation), and induces a RXR alpha conformational change similar to that induced by 9-cis-retinoic acid (as detected by protease sensitivity). These results suggest an involvement of RXR alpha 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.
Lemotte
P K
PK
Department of Dermatology, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Keidel
S
S
Apfel
C M
CM
D001483:Base Sequence; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D010831:Phytanic Acid / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D012035:Refsum Disease / Q000378:metabolism; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism
D008024:Ligands; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D010831:Phytanic Acid; D014212:Tretinoin