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Human Molecular Genetics Advance Access published online on August 22, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi303
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received May 19, 2005
Revised July 19, 2005
Accepted August 2, 2005

Article

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

F. Djouadi 1, F. Aubey 1, D. Schlemmer 1, J. P.N. Ruiter 2, R. J.A. Wanders 2, A. W. Strauss 3, and J. Bastin PhD4*

1 INSERM U393, Hôpital Necker-Enfants Malades, Paris 75015, France
2 Laboratory for Genetic Metabolic Diseases, Academic Medical Centre, 1105AZ Amsterdam, The Netherlands
3 Vanderbilt Children's Hospital, Nashville TN 37232, USA
4 INSERM U393, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, Paris 75015, France

* To whom correspondence should be addressed.
J. Bastin, E-mail: bastin{at}necker.fr


  Abstract

Inherited defect in Very Long Chain AcylCoA Dehydrogenase (VLCAD), a mitochondrial enzyme catalyzing the initial step of long-chain fatty acid ß-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 have been elucidated but therapeutic approaches are quite limited. In this study we tested the hypothesis that fibrates, acting as agonist of PPARs (peroxisome proliferator activated receptors), might stimulate FAO in VLCAD-deficient cells. We demonstrate that addition of bezafibrate or fenofibric acid in the culture medium induced a dose-dependant (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 500µM bezafibrate for 48 hours. Cell therapy of VLCAD deficiency was related to drug-induced increases in VLCAD mRNA (+44 to + 150%; p < 0.001), protein (1.5- to 2-fold), and residual enzyme activity (up to 7.7-fold) in patient cells. Bezafibrate also diminished by 90% the production of toxic long-chain acylcarnitines in cells harboring moderate VLCAD deficiency. Finally, RT-PCR studies indicated that bezafibrate potentially stimulated gene expression of other enzymes in the ß-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.


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