{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:57:01Z","timestamp":1790773021739,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2017,4,10]],"date-time":"2017-04-10T00:00:00Z","timestamp":1491782400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:p>\n                    Alpha1\u2010antitrypsin deficiency is a genetic disease that can affect both the lung and the liver. The vast majority of patients harbor a mutation in the serine protease inhibitor 1A (\n                    <jats:italic toggle=\"yes\">SERPINA1<\/jats:italic>\n                    ) gene leading to a single amino acid substitution that results in an unfolded protein that is prone to polymerization. Alpha1\u2010antitrypsin defciency\u2010related liver disease is therefore caused by a gain\u2010of\u2010function mechanism due to accumulation of the mutant Z alpha1\u2010antitrypsin (ATZ) and is a key example of an disease mechanism induced by protein toxicity. Intracellular retention of ATZ triggers a complex injury cascade including apoptosis and other mechanisms, although several aspects of the disease pathogenesis are still unclear. We show that ATZ induces activation of c\u2010Jun N\u2010terminal kinase (JNK) and c\u2010Jun and that genetic ablation of JNK1 or JNK2 decreased ATZ levels\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    by reducing c\u2010Jun\u2013mediated\n                    <jats:italic toggle=\"yes\">SERPINA1<\/jats:italic>\n                    gene expression. JNK activation was confirmed in livers of patients homozygous for the Z allele, with severe liver disease requiring hepatic transplantation. Treatment of patient\u2010derived induced pluripotent stem cell\u2010hepatic cells with a JNK inhibitor reduced accumulation of ATZ.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : These data reveal that JNK is a key pathway in the disease pathogenesis and add new therapeutic entry points for liver disease caused by ATZ. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2017;65:1865\u20101874).\n                  <\/jats:p>","DOI":"10.1002\/hep.29035","type":"journal-article","created":{"date-parts":[[2017,1,10]],"date-time":"2017-01-10T18:03:22Z","timestamp":1484071402000},"page":"1865-1874","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":27,"title":["Activation of the c\u2010Jun N\u2010terminal kinase pathway aggravates proteotoxicity of hepatic mutant Z alpha1\u2010antitrypsin"],"prefix":"10.1097","volume":"65","author":[{"given":"Nunzia","family":"Pastore","sequence":"first","affiliation":[{"name":"Telethon Institute of Genetics and Medicine,Pozzuoli,Naples,Italy"},{"name":"Department of Molecular and Human Genetics,Baylor College of Medicine,Houston,TX"},{"name":"Jan and Dan Duncan Neurological Research Institute,Texas Children's Hospital,Houston,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Attanasio","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine,Pozzuoli,Naples,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Granese","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine,Pozzuoli,Naples,Italy"},{"name":"Department of Translational Medicine,Federico II University,Naples,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Castello","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine,Pozzuoli,Naples,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Teckman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,Saint Louis University School of Medicine, Cardinal Glennon Children's Medical Center,Saint Louis,MO,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Boston University Center for Regenerative Medicine of Boston University and Boston Medical Center,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ballabio","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine,Pozzuoli,Naples,Italy"},{"name":"Department of Molecular and Human Genetics,Baylor College of Medicine,Houston,TX"},{"name":"Jan and Dan Duncan Neurological Research Institute,Texas Children's Hospital,Houston,TX"},{"name":"Department of Translational Medicine,Federico II University,Naples,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Brunetti\u2010Pierri","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine,Pozzuoli,Naples,Italy"},{"name":"Department of Translational Medicine,Federico II University,Naples,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,4,10]]},"reference":[{"key":"hep29035-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1378\/chest.122.5.1818","article-title":"Worldwide racial and ethnic distribution of alpha1\u2010antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys","volume":"122","year":"2002","journal-title":"Chest"},{"key":"hep29035-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"G961","DOI":"10.1152\/ajpgi.2000.279.5.G961","article-title":"Retention of mutant alpha1\u2010antitrypsin Z in endoplasmic reticulum is associated with an autophagic response","volume":"279","year":"2000","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep29035-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"G1156","DOI":"10.1152\/ajpgi.00041.2002","article-title":"Fasting in alpha1\u2010antitrypsin deficient liver: constitutive activation of autophagy","volume":"283","year":"2002","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep29035-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1056\/NEJMra010772","article-title":"Alpha1\u2010antitrypsin deficiency\u2014a model for conformational diseases","volume":"346","year":"2002","journal-title":"N Engl J Med"},{"key":"hep29035-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1378\/chest.128.4.2076","article-title":"Alpha1\u2010antitrypsin deficiency in 26\u2010year\u2010old subjects: lung, liver, and protease\/protease inhibitor studies","volume":"128","year":"2005","journal-title":"Chest"},{"key":"hep29035-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1056\/NEJM198603203141202","article-title":"Risk of cirrhosis and primary liver cancer in alpha 1\u2010antitrypsin deficiency","volume":"314","year":"1986","journal-title":"N Engl J Med"},{"key":"hep29035-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1172\/JCI113999","article-title":"Accumulation of PiZ alpha 1\u2010antitrypsin causes liver damage in transgenic mice","volume":"83","year":"1989","journal-title":"J Clin Invest"},{"key":"hep29035-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1126\/science.1190354","article-title":"An autophagy\u2010enhancing drug promotes degradation of mutant alpha1\u2010antitrypsin Z and reduces hepatic fibrosis","volume":"329","year":"2010","journal-title":"Science"},{"key":"hep29035-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1002\/emmm.201202046","article-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","volume":"5","year":"2013","journal-title":"EMBO Mol Med"},{"key":"hep29035-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"e87260","DOI":"10.1371\/journal.pone.0087260","article-title":"Fluphenazine reduces proteotoxicity in C. elegans and mammalian models of alpha\u20101\u2010antitrypsin deficiency","volume":"9","year":"2014","journal-title":"PLoS One"},{"key":"hep29035-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1258\/ebm.2010.009297","article-title":"Rapamycin reduces intrahepatic alpha\u20101\u2010antitrypsin mutant Z protein polymers and liver injury in a mouse model","volume":"235","year":"2010","journal-title":"Exp Biol Med (Maywood)"},{"key":"hep29035-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1172\/JCI113580","article-title":"Multiple tissues express alpha 1\u2010antitrypsin in transgenic mice and man","volume":"82","year":"1988","journal-title":"J Clin Invest"},{"key":"hep29035-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/biostatistics\/4.2.249","article-title":"Exploration, normalization, and summaries of high density oligonucleotide array probe level data","volume":"4","year":"2003","journal-title":"Biostatistics"},{"key":"hep29035-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"R80","DOI":"10.1186\/gb-2004-5-10-r80","article-title":"Bioconductor: open software development for computational biology and bioinformatics","volume":"5","year":"2004","journal-title":"Genome Biol"},{"key":"hep29035-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/bioinformatics\/btg405","article-title":"affy\u2014analysis of Affymetrix GeneChip data at the probe level","volume":"20","year":"2004","journal-title":"Bioinformatics"},{"key":"hep29035-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1093\/bioinformatics\/17.6.509","article-title":"A Bayesian framework for the analysis of microarray expression data: regularized t\u2010test and statistical inferences of gene changes","volume":"17","year":"2001","journal-title":"Bioinformatics"},{"key":"hep29035-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1124\/mol.114.092585","article-title":"Regulation of human CYP2C9 expression by electrophilic stress involves activator protein 1 activation and DNA looping","volume":"86","year":"2014","journal-title":"Mol Pharmacol"},{"key":"hep29035-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1002\/stem.495","article-title":"Generation of transgene\u2010free lung disease\u2010specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette","volume":"28","year":"2010","journal-title":"Stem Cells"},{"key":"hep29035-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1182\/blood-2013-02-484444","article-title":"Clonal genetic and hematopoietic heterogeneity among human\u2010induced pluripotent stem cell lines","volume":"122","year":"2013","journal-title":"Blood"},{"key":"hep29035-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.stemcr.2015.02.021","article-title":"Emergence of a stage\u2010dependent human liver disease signature with directed differentiation of alpha\u20101 antitrypsin\u2010deficient iPS cells","volume":"4","year":"2015","journal-title":"Stem Cell Reports"},{"key":"hep29035-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/0092-8674(94)90380-8","article-title":"JNK1: a protein kinase stimulated by UV light and Ha\u2010Ras that binds and phosphorylates the c\u2010Jun activation domain","volume":"76","year":"1994","journal-title":"Cell"},{"key":"hep29035-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1002\/hep.21822","article-title":"Alpha\u20101\u2010antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model","volume":"46","year":"2007","journal-title":"Hepatology"},{"key":"hep29035-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1126\/science.282.5396.2092","article-title":"Defective T cell differentiation in the absence of Jnk1","volume":"282","year":"1998","journal-title":"Science"},{"key":"hep29035-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S1074-7613(00)80640-8","article-title":"Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2","volume":"9","year":"1998","journal-title":"Immunity"},{"key":"hep29035-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"2767","DOI":"10.1002\/j.1460-2075.1987.tb02571.x","article-title":"The human alpha 1\u2010antitrypsin gene is transcribed from two different promoters in macrophages and hepatocytes","volume":"6","year":"1987","journal-title":"EMBO J"},{"key":"hep29035-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1016\/S1357-2725(97)00118-0","article-title":"Regulation of the serine proteinase inhibitor (SERPIN) gene alpha 1\u2010antitrypsin: a paradigm for other SERPINs","volume":"29","year":"1997","journal-title":"Int J Biochem Cell Biol"},{"key":"hep29035-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"16483","DOI":"10.1074\/jbc.270.28.16483","article-title":"The regulation of AP\u20101 activity by mitogen\u2010activated protein kinases","volume":"270","year":"1995","journal-title":"J Biol Chem"},{"key":"hep29035-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1053\/j.gastro.2012.06.004","article-title":"A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches","volume":"143","year":"2012","journal-title":"Gastroenterology"},{"key":"hep29035-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nrc2694","article-title":"Signal integration by JNK and p38 MAPK pathways in cancer development","volume":"9","year":"2009","journal-title":"Nat Rev Cancer"},{"key":"hep29035-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1042\/bst0300093","article-title":"Gene regulation of the serine proteinase inhibitors alpha1\u2010antitrypsin and alpha1\u2010antichymotrypsin","volume":"30","year":"2002","journal-title":"Biochem Soc Trans"},{"key":"hep29035-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"907","DOI":"10.3109\/00365528509088844","article-title":"Liver disease in alpha 1-antitrypsin deficiency. Aspects of incidence and prognosis","volume":"20","year":"1985","journal-title":"Scand J Gastroenterol"},{"key":"hep29035-bib-0032-20241017","first-page":"127","article-title":"Sequential changes of plasma proteins after surgical trauma","volume":"124","year":"1972","journal-title":"Scand J Clin Lab Invest Suppl"},{"key":"hep29035-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1165\/ajrcmb.18.4.2772","article-title":"Oncostatin M is a potent stimulator of alpha1\u2010antitrypsin secretion in lung epithelial cells: modulation by transforming growth factor\u2010beta and interferon\u2010gamma","volume":"18","year":"1998","journal-title":"Am J Respir Cell Mol Biol"},{"key":"hep29035-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1111\/cmi.12071","article-title":"Transcription factor complex AP\u20101 mediates inflammation initiated by Chlamydia pneumoniae infection","volume":"15","year":"2013","journal-title":"Cell Microbiol"},{"key":"hep29035-bib-0035-20241017","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1101\/gad.543109","article-title":"TNFalpha shedding and epidermal inflammation are controlled by Jun proteins","volume":"23","year":"2009","journal-title":"Genes Dev"},{"key":"hep29035-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"4538","DOI":"10.4049\/jimmunol.0802864","article-title":"Evidence for unfolded protein response activation in monocytes from individuals with alpha\u20101 antitrypsin deficiency","volume":"184","year":"2010","journal-title":"J Immunol"},{"key":"hep29035-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1164\/rccm.201306-1151OC","article-title":"miR\u2010199a\u20105p silencing regulates the unfolded protein response in COPD and alpha1 antitrypsin deficiency","volume":"189","year":"2014","journal-title":"Am J Respir Crit Care Med"},{"key":"hep29035-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"39002","DOI":"10.1074\/jbc.M508652200","article-title":"Accumulation of mutant alpha1\u2010antitrypsin Z in the endoplasmic reticulum activates caspases\u20104 and \u201012, NFkappaB, and BAP31 but not the unfolded protein response","volume":"280","year":"2005","journal-title":"J Biol Chem"},{"key":"hep29035-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"20463","DOI":"10.1016\/S0021-9258(17)30527-6","article-title":"Accumulation of the insoluble PiZ variant of human alpha 1\u2010antitrypsin within the hepatic endoplasmic reticulum does not elevate the steady\u2010state level of grp78\/BiP","volume":"265","year":"1990","journal-title":"J Biol Chem"},{"key":"hep29035-bib-0040-20241017","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1126\/science.275.5296.90","article-title":"Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK\/JNK and p38 signaling pathways","volume":"275","year":"1997","journal-title":"Science"},{"key":"hep29035-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0092-8674(00)00116-1","article-title":"Signal transduction by the JNK group of MAP kinases","volume":"103","year":"2000","journal-title":"Cell"},{"key":"hep29035-bib-0042-20241017","doi-asserted-by":"crossref","first-page":"10544","DOI":"10.1073\/pnas.0603499103","article-title":"Loss of hepatic NF\u2010kappa B activity enhances chemical hepatocarcinogenesis through sustained c\u2010Jun N\u2010terminal kinase 1 activation","volume":"103","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"hep29035-bib-0043-20241017","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/ng2033","article-title":"p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK\u2010c\u2010Jun pathway","volume":"39","year":"2007","journal-title":"Nat Genet"},{"key":"hep29035-bib-0044-20241017","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.1172\/JCI37156","article-title":"Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1\u2010dependent p21 downregulation","volume":"118","year":"2008","journal-title":"J Clin Invest"},{"key":"hep29035-bib-0045-20241017","first-page":"181","article-title":"Liver tumor development. c\u2010Jun antagonizes the proapoptotic activity of p53","volume":"112","year":"2003","journal-title":"Cell"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.29035","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201706000-00016","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T19:49:15Z","timestamp":1729194555000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201706000-00016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,10]]},"references-count":45,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.29035","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,10]]},"assertion":[{"value":"2016-11-02","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-12-23","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}