Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency.
Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency.
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主自噬调节剂TFEB的基因转移导致毒性蛋白质的清除和抗甲型抗肌蛋白缺乏症中肝病的校正。
DOI：
10.1002/emmm.201202046
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发表时间：
2013-03
影响因子：
11.1
通讯作者：
Brunetti-Pierri, Nicola
中科院分区：
文献类型：
--
作者：
Pastore, Nunzia;Blomenkamp, Keith;Annunziata, Fabio;Piccolo, Pasquale;Mithbaokar, Pratibha;Sepe, Rosa Maria;Vetrini, Francesco;Palmer, Donna;Ng, Philip;Polishchuk, Elena;Iacobacci, Simona;Polishchuk, Roman;Teckman, Jeffrey;Ballabio, Andrea;Brunetti-Pierri, Nicola
α-1-抗胰蛋白酶缺乏症是儿童肝脏疾病最常见的遗传原因，肝移植是目前唯一可用的治疗方法。肝脏自噬的增强增加了突变型肝毒性α-1-抗胰蛋白酶（ATZ）的降解。我们在PiZ转基因小鼠中研究了转录因子EB（TFEB）的肝脏定向基因转移的治疗潜力，TFEB是一种调节溶酶体功能和自噬的主基因，重现了人类肝脏疾病。肝细胞TFEB基因转移导致肝ATZ、肝细胞凋亡和肝纤维化的显著减少，这是α-1-抗胰蛋白酶缺乏的关键特征。肝脏表型的纠正是由自噬通量增强介导的ATZ聚合物降解增加和由驱动ATZ基因表达的肝脏NFκB活化和IL-6降低介导的ATZ单体减少引起的。总之，TFEB基因转移是治疗α-1-抗胰蛋白酶缺乏性肝病的一种新策略。这项研究可能为TFEB基因转移用于治疗由于细胞内毒性蛋白积累而引起的广泛人类疾病铺平道路。
Alpha-1-anti-trypsin deficiency is the most common genetic cause of liver disease in children and liver transplantation is currently the only available treatment. Enhancement of liver autophagy increases degradation of mutant, hepatotoxic alpha-1-anti-trypsin (ATZ). We investigated the therapeutic potential of liver-directed gene transfer of transcription factor EB (TFEB), a master gene that regulates lysosomal function and autophagy, in PiZ transgenic mice, recapitulating the human hepatic disease. Hepatocyte TFEB gene transfer resulted in dramatic reduction of hepatic ATZ, liver apoptosis and fibrosis, which are key features of alpha-1-anti-trypsin deficiency. Correction of the liver phenotype resulted from increased ATZ polymer degradation mediated by enhancement of autophagy flux and reduced ATZ monomer by decreased hepatic NFκB activation and IL-6 that drives ATZ gene expression. In conclusion, TFEB gene transfer is a novel strategy for treatment of liver disease of alpha-1-anti-trypsin deficiency. This study may pave the way towards applications of TFEB gene transfer for treatment of a wide spectrum of human disorders due to intracellular accumulation of toxic proteins.
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影响因子：
158.5
作者：
ERIKSSON, S;CARLSON, J;VELEZ, R
通讯作者：
VELEZ, R
影响因子：
64.8
作者：
Grimm, Dirk;Streetz, Konrad L.;Kay, Mark A.
通讯作者：
Kay, Mark A.
影响因子：
13.5
作者：
An, JK;Blomenkamp, K;Teckman, JH
通讯作者：
Teckman, JH
影响因子：
12.4
作者：
Brunetti-Pierri, Nicola;Stapleton, Gary E.;Ng, Philip
通讯作者：
Ng, Philip
影响因子：
29.4
作者：
Duan, YY;Wu, J;Zern, MA
通讯作者：
Zern, MA