Correction of fatty acid oxidation in carnitine palmitoyl transferase 2-deficient cultured skin fibroblasts by bezafibrate

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 m...

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Veröffentlicht in:Pediatric research 2003-10, Vol.54 (4), p.446-451
Hauptverfasser: DJOUADI, Fatima, BONNEFONT, Jean-Paul, THUILLIER, Laure, DRCIN, Véronique, KHADOM, Noman, MUNNICH, Arnold, BASTIN, Jean
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container_end_page 451
container_issue 4
container_start_page 446
container_title Pediatric research
container_volume 54
creator DJOUADI, Fatima
BONNEFONT, Jean-Paul
THUILLIER, Laure
DRCIN, Véronique
KHADOM, Noman
MUNNICH, Arnold
BASTIN, Jean
description 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.
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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. 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subjects Bezafibrate - pharmacology
Biological and medical sciences
Carnitine O-Palmitoyltransferase - deficiency
Carnitine O-Palmitoyltransferase - genetics
Carnitine O-Palmitoyltransferase - metabolism
Cells, Cultured
Dose-Response Relationship, Drug
Fatty Acids - metabolism
Fibroblasts - cytology
Fibroblasts - drug effects
Fibroblasts - metabolism
Fundamental and applied biological sciences. Psychology
General aspects
Genetics of eukaryotes. Biological and molecular evolution
Humans
Hypolipidemic Agents - pharmacology
Life Sciences
Medical sciences
Molecular and cellular biology
Oxidation-Reduction
Skin - cytology
title Correction of fatty acid oxidation in carnitine palmitoyl transferase 2-deficient cultured skin fibroblasts by bezafibrate
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