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Start Over Author "Djouadi, Fatima" Journal journal of inherited metabolic disease
6 results on '"Djouadi, Fatima"'

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

Author

Djouadi, Fatima, primary, Habarou, Florence, additional, Le Bachelier, Carole, additional, Ferdinandusse, Sacha, additional, Schlemmer, Dimitri, additional, Benoist, Jean François, additional, Boutron, Audrey, additional, Andresen, Brage S., additional, Visser, Gepke, additional, de Lonlay, Pascale, additional, Olpin, Simon, additional, Fukao, Toshiyuki, additional, Yamaguchi, Seiji, additional, Strauss, Arnold W., additional, Wanders, Ronald J. A., additional, and Bastin, Jean, additional

Published
2015
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3. Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate.

Author

Djouadi, Fatima, Habarou, Florence, Bachelier, Carole, Ferdinandusse, Sacha, Schlemmer, Dimitri, Benoist, Jean, Boutron, Audrey, Andresen, Brage, Visser, Gepke, Lonlay, Pascale, Olpin, Simon, Fukao, Toshiyuki, Yamaguchi, Seiji, Strauss, Arnold, Wanders, Ronald, and Bastin, Jean

Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2016
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5. Mitochondrial trifunctional protein deficiency in human cultured fibroblasts : effects of bezafibrate

Author

Simon E. Olpin, Pascale de Lonlay, A. Boutron, Dimitri Schlemmer, Sacha Ferdinandusse, Carole Le Bachelier, J.F. Benoist, Toshiyuki Fukao, Jean Bastin, Seiji Yamaguchi, Brage S. Andresen, Ronald J.A. Wanders, Florence Habarou, Arnold W. Strauss, Fatima Djouadi, Gepke Visser, Djouadi, Fatima, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratory Genetic Metabolic Diseases [Academic Medical Centre], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Centre Référence des Maladies Héréditaires du Métabolisme [Paris-Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Service de neurologie, maladies métaboliques, Département de Biochimie [AP-HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Biochimie [AP-HP Hôpital Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), University of Southern Denmark (SDU), Wilhelmina Children's Hospital [Utrecht, The Netherlands], University Medical Center [Utrecht], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sheffield Children's NHS Foundation Trust, Gifu University Graduate School of Medicine, Shimane University, Cincinnati Children's Hospital Medical Center, Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, and Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Genotype, [SDV]Life Sciences [q-bio], Alpha (ethology), Mitochondrial trifunctional protein deficiency, Mitochondrial trifunctional protein, Biology, medicine.disease_cause, Research Support, Lipid Metabolism, Inborn Errors, Rhabdomyolysis, Cell Line, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetics, Journal Article, Humans, Genetics(clinical), Non-U.S. Gov't, Beta oxidation, Genetics (clinical), G alpha subunit, Hypolipidemic Agents, Mutation, Bezafibrate, Mitochondrial Trifunctional Protein, Research Support, Non-U.S. Gov't, Mitochondrial Myopathies, Fibroblasts, medicine.disease, Molecular biology, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Biochemistry, Mitochondrial Trifunctional Protein, beta Subunit, biology.protein, Mitochondrial Trifunctional Protein, alpha Subunit, Nervous System Diseases, Cardiomyopathies, 030217 neurology & neurosurgery, HADHB, medicine.drug
Abstract

International audience; 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.

Published
2016

6. Potential of fibrates in the treatment of fatty acid oxidation disorders: Revival of classical drugs?

Author

Jean-Paul Bonnefont, D Schlemmer, R. J. A. Wanders, Arnold W. Strauss, F Aubey, P Laforet, Stéphanie Gobin, Jean Bastin, Fatima Djouadi, Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Vanderbilt University [Nashville], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Djouadi, Fatima

Subjects
[SDV]Life Sciences [q-bio], Pharmacology, GW0742, Lipid Metabolism, Inborn Errors, Clofibric Acid, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, RNA, Messenger, Beta oxidation, Cells, Cultured, Genetics (clinical), Hypolipidemic Agents, 030304 developmental biology, 0303 health sciences, Carnitine O-Palmitoyltransferase, biology, Chemistry, Acyl-CoA Dehydrogenase, Long-Chain, Fatty Acids, digestive, oral, and skin physiology, food and beverages, Fibroblasts, Enzyme assay, Mitochondria, 3. Good health, [SDV] Life Sciences [q-bio], PPAR gamma, Biochemistry, Enzyme Induction, biology.protein, Treatment strategy, Bezafibrate, Oxidation-Reduction, 030217 neurology & neurosurgery
Abstract

International audience; Exposure to fibrates leads to normalization of fatty acid oxidation (FAO) in fibroblasts from patients with myopathic forms of CPT2 deficiency or VLCAD deficiency. Correction of FAO is related to a drug-induced increase of residual enzyme activity, and this could provide a new treatment strategy for these disorders.

Published
2005

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