Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate
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...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Djouadi, Fatima [verfasserIn] Habarou, Florence [verfasserIn] Le Bachelier, Carole [verfasserIn] Ferdinandusse, Sacha [verfasserIn] Schlemmer, Dimitri [verfasserIn] Benoist, Jean François [verfasserIn] Boutron, Audrey [verfasserIn] Andresen, Brage S. [verfasserIn] Visser, Gepke [verfasserIn] de Lonlay, Pascale [verfasserIn] Olpin, Simon [verfasserIn] Fukao, Toshiyuki [verfasserIn] Yamaguchi, Seiji [verfasserIn] Strauss, Arnold W. [verfasserIn] Wanders, Ronald J. A. [verfasserIn] Bastin, Jean [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2015 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Journal of inherited metabolic disease - Hoboken, NJ : Wiley, 1978, 39(2015), 1 vom: 25. Juni, Seite 47-58 |
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| Übergeordnetes Werk: |
volume:39 ; year:2015 ; number:1 ; day:25 ; month:06 ; pages:47-58 |
| Links: |
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| DOI / URN: |
10.1007/s10545-015-9871-3 |
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| Katalog-ID: |
SPR011028785 |
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| 100 | 1 | |a Djouadi, Fatima |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate |
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| 520 | |a 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. | ||
| 650 | 4 | |a Fatty Acid Oxidation |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Bezafibrate |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Control Fibroblast |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Patient Fibroblast |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Fatty Acid Oxidation Disorder |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Habarou, Florence |e verfasserin |4 aut | |
| 700 | 1 | |a Le Bachelier, Carole |e verfasserin |4 aut | |
| 700 | 1 | |a Ferdinandusse, Sacha |e verfasserin |4 aut | |
| 700 | 1 | |a Schlemmer, Dimitri |e verfasserin |4 aut | |
| 700 | 1 | |a Benoist, Jean François |e verfasserin |4 aut | |
| 700 | 1 | |a Boutron, Audrey |e verfasserin |4 aut | |
| 700 | 1 | |a Andresen, Brage S. |e verfasserin |4 aut | |
| 700 | 1 | |a Visser, Gepke |e verfasserin |4 aut | |
| 700 | 1 | |a de Lonlay, Pascale |e verfasserin |4 aut | |
| 700 | 1 | |a Olpin, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Fukao, Toshiyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Yamaguchi, Seiji |e verfasserin |4 aut | |
| 700 | 1 | |a Strauss, Arnold W. |e verfasserin |4 aut | |
| 700 | 1 | |a Wanders, Ronald J. A. |e verfasserin |4 aut | |
| 700 | 1 | |a Bastin, Jean |e verfasserin |4 aut | |
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10.1007/s10545-015-9871-3 doi (DE-627)SPR011028785 (SPR)s10545-015-9871-3-e DE-627 ger DE-627 rakwb eng 610 ASE 44.48 bkl 44.33 bkl Djouadi, Fatima verfasserin aut Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Fatty Acid Oxidation (dpeaa)DE-He213 Bezafibrate (dpeaa)DE-He213 Control Fibroblast (dpeaa)DE-He213 Patient Fibroblast (dpeaa)DE-He213 Fatty Acid Oxidation Disorder (dpeaa)DE-He213 Habarou, Florence verfasserin aut Le Bachelier, Carole verfasserin aut Ferdinandusse, Sacha verfasserin aut Schlemmer, Dimitri verfasserin aut Benoist, Jean François verfasserin aut Boutron, Audrey verfasserin aut Andresen, Brage S. verfasserin aut Visser, Gepke verfasserin aut de Lonlay, Pascale verfasserin aut Olpin, Simon verfasserin aut Fukao, Toshiyuki verfasserin aut Yamaguchi, Seiji verfasserin aut Strauss, Arnold W. verfasserin aut Wanders, Ronald J. A. verfasserin aut Bastin, Jean verfasserin aut Enthalten in Journal of inherited metabolic disease Hoboken, NJ : Wiley, 1978 39(2015), 1 vom: 25. Juni, Seite 47-58 (DE-627)320457753 (DE-600)2006875-X 1573-2665 nnns volume:39 year:2015 number:1 day:25 month:06 pages:47-58 https://dx.doi.org/10.1007/s10545-015-9871-3 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.48 ASE 44.33 ASE AR 39 2015 1 25 06 47-58 |
| spelling |
10.1007/s10545-015-9871-3 doi (DE-627)SPR011028785 (SPR)s10545-015-9871-3-e DE-627 ger DE-627 rakwb eng 610 ASE 44.48 bkl 44.33 bkl Djouadi, Fatima verfasserin aut Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Fatty Acid Oxidation (dpeaa)DE-He213 Bezafibrate (dpeaa)DE-He213 Control Fibroblast (dpeaa)DE-He213 Patient Fibroblast (dpeaa)DE-He213 Fatty Acid Oxidation Disorder (dpeaa)DE-He213 Habarou, Florence verfasserin aut Le Bachelier, Carole verfasserin aut Ferdinandusse, Sacha verfasserin aut Schlemmer, Dimitri verfasserin aut Benoist, Jean François verfasserin aut Boutron, Audrey verfasserin aut Andresen, Brage S. verfasserin aut Visser, Gepke verfasserin aut de Lonlay, Pascale verfasserin aut Olpin, Simon verfasserin aut Fukao, Toshiyuki verfasserin aut Yamaguchi, Seiji verfasserin aut Strauss, Arnold W. verfasserin aut Wanders, Ronald J. A. verfasserin aut Bastin, Jean verfasserin aut Enthalten in Journal of inherited metabolic disease Hoboken, NJ : Wiley, 1978 39(2015), 1 vom: 25. Juni, Seite 47-58 (DE-627)320457753 (DE-600)2006875-X 1573-2665 nnns volume:39 year:2015 number:1 day:25 month:06 pages:47-58 https://dx.doi.org/10.1007/s10545-015-9871-3 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.48 ASE 44.33 ASE AR 39 2015 1 25 06 47-58 |
| allfields_unstemmed |
10.1007/s10545-015-9871-3 doi (DE-627)SPR011028785 (SPR)s10545-015-9871-3-e DE-627 ger DE-627 rakwb eng 610 ASE 44.48 bkl 44.33 bkl Djouadi, Fatima verfasserin aut Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Fatty Acid Oxidation (dpeaa)DE-He213 Bezafibrate (dpeaa)DE-He213 Control Fibroblast (dpeaa)DE-He213 Patient Fibroblast (dpeaa)DE-He213 Fatty Acid Oxidation Disorder (dpeaa)DE-He213 Habarou, Florence verfasserin aut Le Bachelier, Carole verfasserin aut Ferdinandusse, Sacha verfasserin aut Schlemmer, Dimitri verfasserin aut Benoist, Jean François verfasserin aut Boutron, Audrey verfasserin aut Andresen, Brage S. verfasserin aut Visser, Gepke verfasserin aut de Lonlay, Pascale verfasserin aut Olpin, Simon verfasserin aut Fukao, Toshiyuki verfasserin aut Yamaguchi, Seiji verfasserin aut Strauss, Arnold W. verfasserin aut Wanders, Ronald J. A. verfasserin aut Bastin, Jean verfasserin aut Enthalten in Journal of inherited metabolic disease Hoboken, NJ : Wiley, 1978 39(2015), 1 vom: 25. Juni, Seite 47-58 (DE-627)320457753 (DE-600)2006875-X 1573-2665 nnns volume:39 year:2015 number:1 day:25 month:06 pages:47-58 https://dx.doi.org/10.1007/s10545-015-9871-3 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.48 ASE 44.33 ASE AR 39 2015 1 25 06 47-58 |
| allfieldsGer |
10.1007/s10545-015-9871-3 doi (DE-627)SPR011028785 (SPR)s10545-015-9871-3-e DE-627 ger DE-627 rakwb eng 610 ASE 44.48 bkl 44.33 bkl Djouadi, Fatima verfasserin aut Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Fatty Acid Oxidation (dpeaa)DE-He213 Bezafibrate (dpeaa)DE-He213 Control Fibroblast (dpeaa)DE-He213 Patient Fibroblast (dpeaa)DE-He213 Fatty Acid Oxidation Disorder (dpeaa)DE-He213 Habarou, Florence verfasserin aut Le Bachelier, Carole verfasserin aut Ferdinandusse, Sacha verfasserin aut Schlemmer, Dimitri verfasserin aut Benoist, Jean François verfasserin aut Boutron, Audrey verfasserin aut Andresen, Brage S. verfasserin aut Visser, Gepke verfasserin aut de Lonlay, Pascale verfasserin aut Olpin, Simon verfasserin aut Fukao, Toshiyuki verfasserin aut Yamaguchi, Seiji verfasserin aut Strauss, Arnold W. verfasserin aut Wanders, Ronald J. A. verfasserin aut Bastin, Jean verfasserin aut Enthalten in Journal of inherited metabolic disease Hoboken, NJ : Wiley, 1978 39(2015), 1 vom: 25. Juni, Seite 47-58 (DE-627)320457753 (DE-600)2006875-X 1573-2665 nnns volume:39 year:2015 number:1 day:25 month:06 pages:47-58 https://dx.doi.org/10.1007/s10545-015-9871-3 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.48 ASE 44.33 ASE AR 39 2015 1 25 06 47-58 |
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10.1007/s10545-015-9871-3 doi (DE-627)SPR011028785 (SPR)s10545-015-9871-3-e DE-627 ger DE-627 rakwb eng 610 ASE 44.48 bkl 44.33 bkl Djouadi, Fatima verfasserin aut Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Fatty Acid Oxidation (dpeaa)DE-He213 Bezafibrate (dpeaa)DE-He213 Control Fibroblast (dpeaa)DE-He213 Patient Fibroblast (dpeaa)DE-He213 Fatty Acid Oxidation Disorder (dpeaa)DE-He213 Habarou, Florence verfasserin aut Le Bachelier, Carole verfasserin aut Ferdinandusse, Sacha verfasserin aut Schlemmer, Dimitri verfasserin aut Benoist, Jean François verfasserin aut Boutron, Audrey verfasserin aut Andresen, Brage S. verfasserin aut Visser, Gepke verfasserin aut de Lonlay, Pascale verfasserin aut Olpin, Simon verfasserin aut Fukao, Toshiyuki verfasserin aut Yamaguchi, Seiji verfasserin aut Strauss, Arnold W. verfasserin aut Wanders, Ronald J. A. verfasserin aut Bastin, Jean verfasserin aut Enthalten in Journal of inherited metabolic disease Hoboken, NJ : Wiley, 1978 39(2015), 1 vom: 25. Juni, Seite 47-58 (DE-627)320457753 (DE-600)2006875-X 1573-2665 nnns volume:39 year:2015 number:1 day:25 month:06 pages:47-58 https://dx.doi.org/10.1007/s10545-015-9871-3 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.48 ASE 44.33 ASE AR 39 2015 1 25 06 47-58 |
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Enthalten in Journal of inherited metabolic disease 39(2015), 1 vom: 25. Juni, Seite 47-58 volume:39 year:2015 number:1 day:25 month:06 pages:47-58 |
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Fatty Acid Oxidation Bezafibrate Control Fibroblast Patient Fibroblast Fatty Acid Oxidation Disorder |
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Djouadi, Fatima @@aut@@ Habarou, Florence @@aut@@ Le Bachelier, Carole @@aut@@ Ferdinandusse, Sacha @@aut@@ Schlemmer, Dimitri @@aut@@ Benoist, Jean François @@aut@@ Boutron, Audrey @@aut@@ Andresen, Brage S. @@aut@@ Visser, Gepke @@aut@@ de Lonlay, Pascale @@aut@@ Olpin, Simon @@aut@@ Fukao, Toshiyuki @@aut@@ Yamaguchi, Seiji @@aut@@ Strauss, Arnold W. @@aut@@ Wanders, Ronald J. A. @@aut@@ Bastin, Jean @@aut@@ |
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Djouadi, Fatima |
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Djouadi, Fatima ddc 610 bkl 44.48 bkl 44.33 misc Fatty Acid Oxidation misc Bezafibrate misc Control Fibroblast misc Patient Fibroblast misc Fatty Acid Oxidation Disorder Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate |
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610 ASE 44.48 bkl 44.33 bkl Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate Fatty Acid Oxidation (dpeaa)DE-He213 Bezafibrate (dpeaa)DE-He213 Control Fibroblast (dpeaa)DE-He213 Patient Fibroblast (dpeaa)DE-He213 Fatty Acid Oxidation Disorder (dpeaa)DE-He213 |
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ddc 610 bkl 44.48 bkl 44.33 misc Fatty Acid Oxidation misc Bezafibrate misc Control Fibroblast misc Patient Fibroblast misc Fatty Acid Oxidation Disorder |
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Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate |
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Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate |
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Djouadi, Fatima Habarou, Florence Le Bachelier, Carole Ferdinandusse, Sacha Schlemmer, Dimitri Benoist, Jean François Boutron, Audrey Andresen, Brage S. Visser, Gepke de Lonlay, Pascale Olpin, Simon Fukao, Toshiyuki Yamaguchi, Seiji Strauss, Arnold W. Wanders, Ronald J. A. Bastin, Jean |
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mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate |
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Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate |
| abstract |
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. |
| abstractGer |
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_unstemmed |
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. |
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Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR011028785</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519080912.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201005s2015 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s10545-015-9871-3</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR011028785</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s10545-015-9871-3-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">610</subfield><subfield code="q">ASE</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">44.48</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">44.33</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Djouadi, Fatima</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2015</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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. 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