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J Inherit Metab Dis. 2016 Jan;39(1):47-58. doi: 10.1007/s10545-015-9871-3. Epub 2015 Jun 25.

Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate.

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INSERM UMR-1124, Université Paris Descartes, Centre Universitaire des Saints Pères, 45 rue des Saints Pères, 75006, Paris, France.
Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Centre de Référence des Maladies Héréditaires du Métabolisme, Service de Biochimie-Hormonologie, Hôpital Robert Debré, 48 bd Sérurier, 75019, Paris, France.
Service de Biochimie, Hôpital Bicêtre, 78 rue du Général Leclerc, 94270, Le Kremlin Bicêtre, France.
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230, Odense M, Denmark.
Wilhelmina Children's Hospital, University Medical Centre Utrecht, Lundlaan 6, 3584 EA, Utrecht, The Netherlands.
INSERM U781, Institut Imagine des Maladies Génétiques, Université Paris Descartes et Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker, 149 rue de Sèvres, 75015, Paris, France.
Department of Clinical Chemistry, Sheffield Children's Hospital, Western Bank, Sheffield, South Yorkshire, S10 2TH, UK.
Department of Pediatrics, Graduate School of Medicine, Gifu University, Yanagido 1-1, Gifu, 501-1194, Japan.
Department of Pediatrics, Shimane University School of Medicine, 89-1 Enya-Cho, Izumo, 693-8501, Japan.
Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
INSERM UMR-1124, Université Paris Descartes, Centre Universitaire des Saints Pères, 45 rue des Saints Pères, 75006, Paris, France.


Mitochondrial trifunctional protein (MTP) deficiency caused by HADHA or HADHB gene mutations exhibits substantial molecular, biochemical, and clinical heterogeneity and ranks among the more severe fatty acid oxidation (FAO) disorders, without pharmacological treatment. Since bezafibrate has been shown to potentially correct other FAO disorders in patient cells, we analyzed its effects in 26 MTP-deficient patient fibroblasts representing 16 genotypes. Overall, the patient cell lines exhibited variable, complex, biochemical profiles and pharmacological responses. HADHA-deficient fibroblasts showed markedly reduced alpha subunit protein levels together with decreased beta-subunit abundance, exhibited a -86 to -96% defect in LCHAD activity, and produced large amounts of C14 and C16 hydroxyacylcarnitines. In control fibroblasts, exposure to bezafibrate (400 μM for 48 h) increased the abundance of HADHA and HADHB mRNAs, immune-detectable alpha and beta subunit proteins, activities of LCHAD and LCKAT, and stimulated FAO capacities, clearly indicating that MTP is pharmacologically up-regulated by bezafibrate in human fibroblasts. In MTP-deficient patient fibroblasts, which were found markedly FAO-deficient, bezafibrate improved FAO capacities in six of 26 (23%) cases, including three cell lines heterozygous for the common c1528G > C mutation. Altogether, our results strongly suggest that, due to variable effects of HADHA and HADHB mutations on MTP abundance and residual activity, improvement of MTP deficiency in response to bezafibrate was achieved in a subset of responsive genotypes.

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