title: Bezafibrate increases very-long-chain acyl-CoA dehydrogenase protein and mRNA expression in deficient fibroblasts and is a potential therapy for fatty acid oxidation disorders.
abstract: Inherited defect in very-long-chain acyl-CoA dehydrogenase (VLCAD), a mitochondrial enzyme catalyzing the initial step of long-chain fatty acid beta-oxidation (FAO), is one of the most frequent FAO enzyme defects. VLCAD deficiency is associated with clinical manifestations varying in severity, tissue involvement and age of onset. The molecular basis of VLCAD deficiency has been elucidated but therapeutic approaches are quite limited. In this study, we tested the hypothesis that fibrates, acting as agonist of peroxisome proliferator-activated receptors (PPARs), might stimulate FAO in VLCAD-deficient cells. We demonstrate that addition of bezafibrate or fenofibric acid in the culture medium induced a dose-dependent (up to 3-fold) increase in palmitate oxidation capacities in cells from patients with the myopathic form of VLCAD deficiency, but not in cells from severely affected patients. Complete normalization of cell FAO capacities could be achieved after exposure to 500 microm bezafibrate for 48 h. Cell therapy of VLCAD deficiency was related to drug-induced increases in VLCAD mRNA (+44 to +150%; P<0.001), protein (1.5-2-fold) and residual enzyme activity (up to 7.7-fold) in patient cells. Bezafibrate also diminished the production of toxic long-chain acylcarnitines by 90% in cells harboring moderate VLCAD deficiency. Finally, real-time PCR studies indicated that bezafibrate potentially stimulated gene expression of other enzymes in the beta-oxidation pathway. These data highlight the potential of fibrates in the correction of inborn FAO defects, as most mutations associated with these defects are compatible with the synthesis of a mutant protein with variable levels of residual enzyme activity.
authors.affiliation: INSERM U393, Hôpital Necker-Enfants Malades, Paris 75015, France.
authors.forename: F
authors.initials: F
authors.lastname: Djouadi
authors.forename: F
authors.initials: F
authors.lastname: Aubey
authors.forename: D
authors.initials: D
authors.lastname: Schlemmer
authors.forename: J P N
authors.initials: JP
authors.lastname: Ruiter
authors.forename: R J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: A W
authors.initials: AW
authors.lastname: Strauss
authors.forename: Jean
authors.initials: J
authors.lastname: Bastin
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D001629:Bezafibrate / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology; D020125:Mutation, Missense / Q000235:genetics; D010168:Palmitates / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D010168:Palmitates; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; C116917:acylcarnitine; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine; D001629:Bezafibrate