title: Phytanoyl-CoA hydroxylase activity is induced by phytanic acid.
abstract: Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid present in various dietary products such as milk, cheese and fish. In patients with Refsum disease, accumulation of phytanic acid occurs due to a deficiency of phytanoyl-CoA hydroxylase, a peroxisomal enzyme containing a peroxisomal targeting signal 2. Recently, phytanoyl-CoA hydroxylase cDNA has been isolated and functional mutations have been identified. As it has been shown that phytanic acid activates the nuclear hormone receptors peroxisome proliferator-activated receptor (PPAR)alpha and all three retinoid X receptors (RXRs), the intracellular concentration of this fatty acid should be tightly regulated. When various cell lines were grown in the presence of phytanic acid, the activity of phytanoyl-CoA hydroxylase increased up to four times, depending on the particular cell type. In one cell line, HepG2, no induction of phytanoyl-CoA hydroxylase activity was observed. After addition of phytanic acid to COS-1 cells, an increase in phytanoyl-CoA hydroxylase activity was observed within 2 h, indicating a quick cell response. No stimulation of phytanoyl-CoA hydroxylase was observed when COS-1 cells were grown in the presence of clofibric acid, 9-cis-retinoic acid or both ligands together. This indicates that the activation of phytanoyl-CoA hydroxylase is not regulated via PPARalpha or RXR. However, stimulation of PPARalpha and all RXRs by clofibric acid and 9-cis-retinoic acid was observed in transient transfection assays. These results suggest that the induction of phytanoyl-CoA hydroxylase by phytanic acid does not proceed via one of the nuclear hormone receptors, RXR or PPARalpha.
authors.affiliation: Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht, the Netherlands.
authors.forename: A W
authors.initials: AW
authors.lastname: Zomer
authors.forename: G A
authors.initials: GA
authors.lastname: Jansen
authors.forename: B
authors.initials: B
authors.lastname: Van Der Burg
authors.forename: N M
authors.initials: NM
authors.lastname: Verhoeven
authors.forename: C
authors.initials: C
authors.lastname: Jakobs
authors.forename: P T
authors.initials: PT
authors.lastname: Van Der Saag
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: B T
authors.initials: BT
authors.lastname: Poll-The
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D019556:COS Cells; D002417:Cattle; D002995:Clofibric Acid / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010831:Phytanic Acid / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D010831:Phytanic Acid; D000077556:Alitretinoin; D002995:Clofibric Acid; D014212:Tretinoin; D006899:Mixed Function Oxygenases; C102623:PHYH protein, human