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Enhancement of liver autophagy increases degradation of mutant, hepatotoxic alpha\u20101\u2010anti\u2010trypsin (ATZ). We investigated the therapeutic potential of liver\u2010directed 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\u20101\u2010anti\u2010trypsin 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 NF\u03baB activation and IL\u20106 that drives ATZ gene expression. In conclusion, TFEB gene transfer is a novel strategy for treatment of liver disease of alpha\u20101\u2010anti\u2010trypsin 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.<\/jats:p>","DOI":"10.1002\/emmm.201202046","type":"journal-article","created":{"date-parts":[[2013,2,4]],"date-time":"2013-02-04T11:04:53Z","timestamp":1359975893000},"page":"397-412","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":133,"title":["Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha\u20101\u2010anti\u2010trypsin deficiency"],"prefix":"10.1038","volume":"5","author":[{"given":"Nunzia","family":"Pastore","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Blomenkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Annunziata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Piccolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratibha","family":"Mithbaokar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Maria Sepe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Vetrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Polishchuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Iacobacci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Polishchuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Teckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ballabio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Brunetti\u2010Pierri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,2,4]]},"reference":[{"key":"BFEMMM201202046_CR1","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.jhep.2012.02.025","volume":"57","author":"S Alam","year":"2012","unstructured":"Alam S, Wang J, Janciauskiene S, Mahadeva R (2012) Preventing and reversing the cellular consequences of Z alpha\u20101 antitrypsin accumulation by targeting s4A. 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