{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:03:49Z","timestamp":1790553829354,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,6,25]],"date-time":"2015-06-25T00:00:00Z","timestamp":1435190400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2015,6,25]],"date-time":"2015-06-25T00:00:00Z","timestamp":1435190400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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\u2010deficient patient fibroblasts representing 16 genotypes. Overall, the patient cell lines exhibited variable, complex, biochemical profiles and pharmacological responses. HADHA\u2010deficient fibroblasts showed markedly reduced alpha subunit protein levels together with decreased beta\u2010subunit abundance, exhibited a \u221286 to \u221296 % defect in LCHAD activity, and produced large amounts of C14 and C16 hydroxyacylcarnitines. In control fibroblasts, exposure to bezafibrate (400 \u03bcM for 48 h) increased the abundance of HADHA and HADHB mRNAs, immune\u2010detectable alpha and beta subunit proteins, activities of LCHAD and LCKAT, and stimulated FAO capacities, clearly indicating that MTP is pharmacologically up\u2010regulated by bezafibrate in human fibroblasts. In MTP\u2010deficient patient fibroblasts, which were found markedly FAO\u2010deficient, bezafibrate improved FAO capacities in six of 26 (23 %) cases, including three cell lines heterozygous for the common c1528G\u2009&gt;\u2009C 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.<\/jats:p>","DOI":"10.1007\/s10545-015-9871-3","type":"journal-article","created":{"date-parts":[[2015,6,24]],"date-time":"2015-06-24T05:11:41Z","timestamp":1435122701000},"page":"47-58","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate"],"prefix":"10.1002","volume":"39","author":[{"given":"Fatima","family":"Djouadi","sequence":"first","affiliation":[{"name":"INSERM UMR\u20101124, Universit\u00e9 Paris Descartes Centre Universitaire des Saints P\u00e8res 45 rue des Saints P\u00e8res Paris 75006 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Habarou","sequence":"additional","affiliation":[{"name":"INSERM UMR\u20101124, Universit\u00e9 Paris Descartes Centre Universitaire des Saints P\u00e8res 45 rue des Saints P\u00e8res Paris 75006 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Le Bachelier","sequence":"additional","affiliation":[{"name":"INSERM UMR\u20101124, Universit\u00e9 Paris Descartes Centre Universitaire des Saints P\u00e8res 45 rue des Saints P\u00e8res Paris 75006 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sacha","family":"Ferdinandusse","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Centre University of Amsterdam Meibergdreef 9 Amsterdam 1105 AZ The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitri","family":"Schlemmer","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies H\u00e9r\u00e9ditaires du M\u00e9tabolisme, Service de Biochimie\u2010Hormonologie H\u00f4pital Robert Debr\u00e9 48 bd S\u00e9rurier Paris 75019 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean Fran\u00e7ois","family":"Benoist","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies H\u00e9r\u00e9ditaires du M\u00e9tabolisme, Service de Biochimie\u2010Hormonologie H\u00f4pital Robert Debr\u00e9 48 bd S\u00e9rurier Paris 75019 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Boutron","sequence":"additional","affiliation":[{"name":"Service de Biochimie H\u00f4pital Bic\u00eatre 78 rue du G\u00e9n\u00e9ral Leclerc Le Kremlin Bic\u00eatre 94270 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brage S.","family":"Andresen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Southern Denmark Campusvej 55 Odense M DK\u20105230 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gepke","family":"Visser","sequence":"additional","affiliation":[{"name":"Wilhelmina Children's Hospital University Medical Centre Utrecht Lundlaan 6 Utrecht 3584 EA The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"de Lonlay","sequence":"additional","affiliation":[{"name":"INSERM U781, Institut Imagine des Maladies G\u00e9n\u00e9tiques Universit\u00e9 Paris Descartes et Centre de R\u00e9f\u00e9rence des Maladies H\u00e9r\u00e9ditaires du M\u00e9tabolisme, H\u00f4pital Necker 149 rue de S\u00e8vres Paris 75015 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Olpin","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Sheffield Children's Hospital Western Bank Sheffield South Yorkshire S10 2TH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyuki","family":"Fukao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Graduate School of Medicine Gifu University Yanagido 1\u20101 Gifu 501\u20101194 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shimane University School of Medicine 89\u20101 Enya\u2010Cho Izumo 693\u20108501 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnold W.","family":"Strauss","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati OH 45229 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J. 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