{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:13:47Z","timestamp":1787314427678,"version":"build-2736575974"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T00:00:00Z","timestamp":1561334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T00:00:00Z","timestamp":1561334400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:p>\n                    Autophagy is a lysosomal degradation pathway that degrades cytoplasmic proteins and organelles. Absence of autophagy in hepatocytes has been linked to promoting liver injury and tumorigenesis; however, the mechanisms behind why a lack of autophagy induces these complications are not fully understood. The role of mammalian target of rapamycin (mTOR) in impaired autophagy\u2010induced liver pathogenesis and tumorigenesis was investigated by using liver\u2010specific autophagy related 5 knockout (L\u2010ATG5 KO) mice, L\u2010ATG5\/mTOR, and L\u2010ATG5\/Raptor double knockout (DKO) mice. We found that deletion of mTOR or Raptor in L\u2010ATG5 KO mice at 2\u00a0months of age attenuated hepatomegaly, cell death, and inflammation but not fibrosis. Surprisingly, at 6\u00a0months of age, L\u2010ATG5\/mTOR DKO and L\u2010ATG5\/Raptor DKO mice also had increased hepatic inflammation, fibrosis, and liver injury, similar to the L\u2010ATG5 KO mice. Moreover, more than 50% of L\u2010ATG5\/mTOR DKO and L\u2010ATG5\/Raptor DKO mice already developed spontaneous tumors, but none of the L\u2010ATG5 KO mice had developed any tumors at 6\u00a0months of age. At 9\u00a0months of age, all L\u2010ATG5\/mTOR DKO and L\u2010ATG5\/Raptor DKO had developed liver tumors. Mechanistically, L\u2010ATG5\/mTOR DKO and L\u2010ATG5\/Raptor DKO mice had decreased levels of hepatic ubiquitinated proteins and persistent nuclear erythroid 2 p45\u2010related factor 2 activation but had increased Akt activation compared with L\u2010ATG5 KO mice.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    Loss of mTOR signaling attenuates the liver pathogenesis in mice with impaired hepatic autophagy but paradoxically promotes tumorigenesis in mice at a relatively young age. Therefore, the balance of mTOR is critical in regulating the liver pathogenesis and tumorigenesis in mice with impaired hepatic autophagy.\n                  <\/jats:p>","DOI":"10.1002\/hep.30770","type":"journal-article","created":{"date-parts":[[2019,5,16]],"date-time":"2019-05-16T14:49:29Z","timestamp":1558018169000},"page":"2142-2155","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":55,"title":["Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy\u2010Defective Mouse Liver"],"prefix":"10.1097","volume":"70","author":[{"given":"Hong\u2010Min","family":"Ni","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojuan","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, 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City,KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyun","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS"},{"name":"Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai,China"},{"name":"School of Chemical and Biological Engineering,Yichun University,Jiangxi,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health Sciences,University of Washington,Seattle,WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Kansas,Medical Center,Kansas City,KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghong","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Liver Surgery & Transplantation,Liver Cancer Institute, Zhongshan Hospital, Fudan University,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Xing","family":"Zong","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology, Ernest Mario School of Pharmacy,Rutgers University,Piscataway,NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengtao","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese 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History"}},{"value":"2019-05-10","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}