title: Phytanic acid attenuates insulin-like growth factor-1 activity via nitric oxide-mediated γ-secretase activation in rat aortic smooth muscle cells: possible implications for pathogenesis of infantile Refsum disease.
abstract: Infantile Refsum disease (IRD), a peroxisomal disease with defective phytanic acid oxidation, causes neurological impairment and development delay. Insulin-like growth factor-1 (IGF-1) regulates child development and to understand molecular mechanism(s) of IRD, we examined the effect of phytanic acid (PA) on IGF-1 activity.
  
  
  
  Bromodeoxyuridine (BrdU) incorporation was measured in rat aortic smooth muscle cell (SMC) cultures following treatment with fetal bovine serum (FBS), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) or IGF-1 in the absence or presence of PA. Gene expression and protein contents of IGF-1 receptor (IGF-1R) and PDGF receptor (PDGFR) were examined using quantitative PCR and western blotting.
  
  
  
  PA inhibited mitogenic activities of FBS, PDGF and IGF-1 with more pronounced effect on IGF-1-induced bromodeoxyuridine (BrdU) incorporation. Palmitic acid or lignoceric acids did not inhibit IGF-1 activity. PA had no effect on PDGFR mRNA/protein levels but markedly increased IGF-1R mRNA levels. PA and nitric oxide (NO) markedly decreased IGF-1R protein. L-NAME, a NO synthase inhibitor and DAPT, a γ-secretase inhibitor, alleviated PA-induced decrease in IGF-1R protein. Both PA and NO donor increased γ-secretase activity which was alleviated by L-NAME.
  
  
  
  This study demonstrates that PA attenuates IGF-1 activity possibly through IGF-1R impairment and NO-mediated modulation of γ-secretase activity.
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait.
authors.forename: Gursev S
authors.initials: GS
authors.lastname: Dhaunsi
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait.
authors.forename: Mayra
authors.initials: M
authors.lastname: Alsaeid
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Kuwait.
authors.forename: Saghir
authors.initials: S
authors.lastname: Akhtar
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010831:Phytanic Acid / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D052919:Refsum Disease, Infantile / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D010982:Platelet-Derived Growth Factor; D016222:Fibroblast Growth Factor 2; D010831:Phytanic Acid; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D017479:Receptors, Platelet-Derived Growth Factor; D053829:Amyloid Precursor Protein Secretases