Human Molecular Genetics Advance Access originally published online on August 22, 2005
Human Molecular Genetics 2005 14(18):2695-2703; doi:10.1093/hmg/ddi303
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
1INSERM U393, Hôpital Necker-Enfants Malades, Paris 75015, France, 2Laboratory for Genetic Metabolic Diseases, Academic Medical Centre, 1105AZ Amsterdam, The Netherlands and 3Vanderbilt Children's Hospital, Nashville, TN 37232, USA
* To whom correspondence should be addressed at: INSERM U393, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75015 Paris, France. Tel: +33 144495161; Fax: +33 147348514; Email: bastin{at}necker.fr
Received May 19, 2005; Revised July 19, 2005; Accepted August 2, 2005
Inherited defect in very-long-chain acyl-CoA 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 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 µM 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 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.