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.