Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue Journal of Inherited Metabolic Disease Année : 2016

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

Brage Andresen
  • Fonction : Auteur
  • PersonId : 906301
Toshiyuki Fukao
  • Fonction : Auteur
  • PersonId : 922369

Résumé

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.
Fichier sous embargo
Fichier sous embargo
Date de visibilité indéterminée
Loading...

Dates et versions

inserm-02894826 , version 1 (09-07-2020)
inserm-02894826 , version 2 (09-07-2020)

Identifiants

Citer

Fatima Djouadi, Florence Habarou, Carole Le Bachelier, Sacha Ferdinandusse, Dimitri Schlemmer, et al.. Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate. Journal of Inherited Metabolic Disease, 2016, 39, pp.47 - 58. ⟨10.1007/s10545-015-9871-3⟩. ⟨inserm-02894826v1⟩
215 Consultations
272 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More