{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:30:05Z","timestamp":1790746205555,"version":"4.1.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T00:00:00Z","timestamp":1592870400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T00:00:00Z","timestamp":1592870400000},"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":[[2020,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>The proinflammatory cytokine IL\u20101\u03b2 has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL\u20101\u03b2 promotes liver injury in these diseases is unclear, as no IL\u20101\u03b2 receptor\u2010linked death pathway has been identified. Autophagy functions in hepatocyte resistance to injury and death, and findings of decreased hepatic autophagy in many liver diseases suggest a role for impaired autophagy in disease pathogenesis. Recent findings that autophagy blocks mouse liver injury from lipopolysaccharide led to an examination of autophagy\u2019s function in hepatotoxicity from proinflammatory cytokines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      AML12 cells with decreased autophagy from a lentiviral\n                      <jats:italic toggle=\"yes\">autophagy\u2010related 5<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">Atg5<\/jats:italic>\n                      ) knockdown were resistant to toxicity from TNF, but sensitized to death from IL\u20101\u03b2, which was markedly amplified by TNF co\u2010treatment. IL\u20101\u03b2\/TNF death was necrosis by trypan blue and propidium iodide positivity, absence of mitochondrial death pathway and caspase activation, and failure of a caspase inhibitor or necrostatin\u20101s to prevent death. IL\u20101\u03b2\/TNF depleted autophagy\u2010deficient cells of ATP, and ATP depletion and cell death were prevented by supplementation with the energy substrate pyruvate or oleate. Pharmacological inhibitors and genetic knockdown studies demonstrated that IL\u20101\u03b2\/TNF\u2010induced necrosis resulted from lysosomal permeabilization and release of cathepsins B and L in autophagy\u2010deficient cells. Mice with a tamoxifen\u2010inducible, hepatocyte\u2010specific\n                      <jats:italic toggle=\"yes\">Atg5<\/jats:italic>\n                      knockout were similarly sensitized to cathepsin\u2010dependent hepatocellular injury and death from IL\u20101\u03b2\/TNF in combination, but neither IL\u20101\u03b2 nor TNF alone. Knockout mice had increased hepatic inflammation, and IL\u20101\u03b2\/TNF\u2010treated, autophagy\u2010deficient AML12 cells secreted exosomes with proinflammatory damage\u2013associated molecular patterns.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The findings delineate mechanisms by which decreased hepatocyte autophagy promotes IL\u20101\u03b2\/TNF\u2010induced necrosis from impaired energy homeostasis and lysosomal permeabilization and inflammation through the secretion of exosomal damage\u2013associated molecular patterns.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.31209","type":"journal-article","created":{"date-parts":[[2020,2,28]],"date-time":"2020-02-28T10:00:55Z","timestamp":1582884055000},"page":"595-608","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":102,"title":["Decreased Hepatocyte Autophagy Leads to Synergistic IL\u20101\u03b2 and TNF Mouse Liver Injury and Inflammation"],"prefix":"10.1097","volume":"72","author":[{"given":"Yang","family":"Shen","sequence":"first","affiliation":[{"name":"Division of Digestive Diseases,Department of Medicine,Emory University School of Medicine,Atlanta,GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0843-8512","authenticated-orcid":false,"given":"Shoaib Ahmad","family":"Malik","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases,Department of Medicine,Emory University School of Medicine,Atlanta,GA"},{"name":"Department of 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