{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:59:13Z","timestamp":1790247553178,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2018,4,20]],"date-time":"2018-04-20T00:00:00Z","timestamp":1524182400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2018,4,20]],"date-time":"2018-04-20T00:00:00Z","timestamp":1524182400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:p>unc\u201051\u2010like autophagy activating kinase 1 and 2 (Ulk1\/2) regulate autophagy initiation under various stress conditions. However, the physiological functions of these Ser\/Thr kinases are not well characterized. Here, we show that mice with liver\u2010specific double knockout (LDKO) of<jats:italic toggle=\"yes\">Ulk1<\/jats:italic>and<jats:italic toggle=\"yes\">Ulk2<\/jats:italic>(<jats:italic toggle=\"yes\">Ulk1\/2<\/jats:italic>LDKO) are viable, but exhibit overt hepatomegaly phenotype. Surprisingly,<jats:italic toggle=\"yes\">Ulk1\/2<\/jats:italic>LDKO mice display normal autophagic activity in hepatocytes upon overnight fasting, but are strongly resistant to acetaminophen (APAP)\u2010induced liver injury. Further studies revealed that<jats:italic toggle=\"yes\">Ulk1\/2<\/jats:italic>are also dispensable for APAP\u2010induced autophagy process, but are essential for the maximum activation of c\u2010Jun N\u2010terminal kinase (JNK) signaling both<jats:italic toggle=\"yes\">in vivo<\/jats:italic>and in isolated primary hepatocytes during APAP treatment. Mechanistically, APAP\u2010induced inhibition of mechanistic target of rapamycin complex 1 releases Ulk1 from an inactive state. Activated Ulk1 then directly phosphorylates and increases the kinase activity of mitogen\u2010activated protein kinase kinase 4 and 7 (MKK4\/7), the upstream kinases and activator of JNK, and mediates APAP\u2010induced liver injury. Ulk1\u2010dependent phosphorylation of MKK7 was further confirmed by a context\u2010dependent phosphorylation antibody. Moreover, activation of JNK and APAP\u2010induced cell death was markedly attenuated in<jats:italic toggle=\"yes\">Mkk4\/7<\/jats:italic>double knockdown hepatocytes reconstituted with an Ulk1\u2010unphosphorylatable mutant of MKK7 compared to those in cells rescued with wild\u2010type MKK7.<jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>Together, these findings reveal an important role of Ulk1\/2 for APAP\u2010induced JNK activation and liver injury, and understanding of this regulatory mechanism may offer us new strategies for prevention and treatment of human APAP hepatotoxicity. (H<jats:sc>epatology<\/jats:sc>2018;67:2397\u20102413).<\/jats:p>","DOI":"10.1002\/hep.29759","type":"journal-article","created":{"date-parts":[[2017,12,24]],"date-time":"2017-12-24T09:29:39Z","timestamp":1514107779000},"page":"2397-2413","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":36,"title":["Liver\u2010specific deficiency of unc\u201051 like kinase 1 and 2 protects mice from acetaminophen\u2010induced liver injury"],"prefix":"10.1097","volume":"67","author":[{"given":"Yu","family":"Sun","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences,Xiamen University,Fujian,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terytty Yang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences,Xiamen University,Fujian,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lintao","family":"Song","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences,Xiamen University,Fujian,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cixiong","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences,Xiamen University,Fujian,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences,Xiamen University,Fujian,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi\u2010Zhong","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences,Xiamen University,Fujian,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng\u2010Cai","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences,Xiamen University,Fujian,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu\u2010Yong","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences,Xiamen University,Fujian,China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2018,4,20]]},"reference":[{"key":"hep29759-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3949\/ccjm.77a.09084","article-title":"Acetaminophen: old drug, new warnings","volume":"77","year":"2010","journal-title":"Cleve Clin J Med"},{"key":"hep29759-bib-0002-20241017","first-page":"131","article-title":"Acetaminophen\u2010induced hepatotoxicity: a comprehensive update","volume":"4","year":"2016","journal-title":"J Clin Transl Hepatol"},{"key":"hep29759-bib-0003-20241017","first-page":"153","article-title":"Acetaminophen\u2010induced liver injury: from animal models to humans","volume":"2","year":"2014","journal-title":"J Clin Transl Hepatol"},{"key":"hep29759-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/978-3-642-00663-0_12","article-title":"Mechanisms of acetaminophen\u2010induced liver necrosis","volume":"196","year":"2010","journal-title":"Handb Exp Pharmacol"},{"key":"hep29759-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1002\/hep.20948","article-title":"Acetaminophen\u2010induced acute liver failure: results of a United States multicenter, prospective study","volume":"42","year":"2005","journal-title":"Hepatology"},{"key":"hep29759-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1093\/toxsci\/kfi336","article-title":"Intracellular signaling mechanisms of acetaminophen\u2010induced liver cell death","volume":"89","year":"2006","journal-title":"Toxicol Sci"},{"key":"hep29759-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0022-3565(25)29666-5","article-title":"Acetaminophen\u2010induced hepatic necrosis. 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