title: Correction of fatty acid oxidation in carnitine palmitoyl transferase 2-deficient cultured skin fibroblasts by bezafibrate.
abstract: Carnitine palmitoyltransferase 2 (CPTII) deficiency is among the most common inborn errors of mitochondrial fatty acid beta-oxidation (FAO). Clinical phenotype varies in relation to the metabolic block, as assessed by studies of FAO in patient fibroblasts. Thus, fibroblasts from patients with mild manifestations have appreciable residual CPTII enzyme activity, in contrast to those from severely affected patients. In the present study, we hypothesized that the hypolipidemic drug bezafibrate, acting as an activator of the peroxisome proliferator-activated receptor alpha might stimulate FAO in CPTII-deficient cells. Data obtained show that bezafibrate treatment of mild-type CPTII-deficient cells resulted in a time- and dose- dependent increase in CPTII mRNA (from +47% to +66%) and residual enzyme activity (from +54% to 135%), and led to normalization of 3H-palmitate and 3H-myristate cellular oxidation rates. Bezafibrate did not correct FAO in fibroblasts from patients with severe phenotype. This study establishes for the first time that peroxisome proliferator-activated receptor activators, acting via stimulation of gene expression, can stimulate CPTII residual activity to a level sufficient to allow normal FAO flux in deficient human fibroblasts, and suggests that this approach should be tested in other inborn errors of mitochondrial beta-oxidation.
authors.affiliation: INSERM U393, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Fatima
authors.initials: F
authors.lastname: Djouadi
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Bonnefont
authors.forename: Laure
authors.initials: L
authors.lastname: Thuillier
authors.forename: Véronique
authors.initials: V
authors.lastname: Droin
authors.forename: Noman
authors.initials: N
authors.lastname: Khadom
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Jean
authors.initials: J
authors.lastname: Bastin
mesh_terms: D001629:Bezafibrate / Q000494:pharmacology*; D002334:Carnitine O-Palmitoyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D010084:Oxidation-Reduction; D012867:Skin / Q000166:cytology*
chemical_list: D005227:Fatty Acids; D000960:Hypolipidemic Agents; D002334:Carnitine O-Palmitoyltransferase; D001629:Bezafibrate