Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate
Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate
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DOI：
10.1007/s10545-015-9871-3
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发表时间：
2016-01-01
影响因子：
4.2
通讯作者：
Bastin, Jean
中科院分区：
文献类型：
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作者：
Djouadi, Fatima;Habarou, Florence;Bastin, Jean
由HADHA或HADHB基因突变引起的线粒体三功能蛋白（MTP）缺乏表现出大量的分子、生化和临床异质性，是更严重的脂肪酸氧化（FAO）疾病之一，无需药物治疗。由于bezafibrate已被证明可能纠正患者细胞中的其他FAO紊乱，我们分析了其对26例mtp缺陷患者成纤维细胞的影响，这些患者代表16种基因型。总的来说，患者细胞系表现出可变的、复杂的生化特征和药理学反应。缺乏hadha的成纤维细胞显示α亚基蛋白水平和β亚基丰度显著降低，LCHAD活性下降- 86%至- 96%，并产生大量的C14和C16羟基酰基肉碱。在对照成纤维细胞中，暴露于贝扎贝特（400 μ M， 48小时）增加了HADHA和HADHB mrna的丰度、免疫可检测的α和β亚基蛋白、LCHAD和LCKAT的活性，并刺激了FAO能力，清楚地表明，在人成纤维细胞中，MTP被贝扎贝特药理学上调。在发现明显缺乏FAO的mtp缺陷患者成纤维细胞中，26例（23%）病例中有6例（23%）使用贝扎菲特改善了FAO能力，包括常见的c1528G>C突变的3株杂合细胞系。总之，我们的研究结果强烈表明，由于HADHA和HADHB突变对MTP丰度和残留活性的不同影响，在一部分应答基因型中，对贝扎贝特的MTP缺乏症得到了改善。
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 mu M 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.