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This study focuses on the role of autophagy in regulating sensitivity of fatty livers to ischemia and reperfusion (I\/R) injury. Quantitative immunohistochemistry conducted on human liver allograft biopsies showed that, the reduction of autophagy markers LC3 and Beclin-1 at 1\u2009h after reperfusion, was correlated with hepatic steatosis and poor survival of liver transplant recipients. In animal studies, western blotting and confocal imaging analysis associated the increase in sensitivity to I\/R injury with low autophagy activity in fatty livers. Screening of autophagy-related proteins showed that Atg3 and Atg7 expression levels were marked decreased, whereas calpain 2 expression was upregulated during I\/R in fatty livers. Calpain 2 inhibition or knockdown enhanced autophagy and suppressed cell death. Further point mutation experiments revealed that calpain 2 cleaved Atg3 and Atg7 at Atg3\u039492\u201397 and Atg7\u0394344\u2013349, respectively. <jats:italic>In vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> overexpression of Atg3 or Atg7 enhanced autophagy and suppressed cell death after I\/R in fatty livers. Collectively, calpain 2-mediated degradation of Atg3 and Atg7 in fatty livers increases their sensitivity to I\/R injury. Increasing autophagy may ameliorate fatty liver damage and represent a valuable method to expand the liver donor pool.<\/jats:p>","DOI":"10.1038\/cddis.2016.66","type":"journal-article","created":{"date-parts":[[2016,4,14]],"date-time":"2016-04-14T16:08:36Z","timestamp":1460650116000},"page":"e2186-e2186","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Calpain 2-mediated autophagy defect increases susceptibility of fatty livers to ischemia\u2013reperfusion injury"],"prefix":"10.1038","volume":"7","author":[{"given":"Q","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W","family":"Ju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,14]]},"reference":[{"key":"BFcddis201666_CR1","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1016\/j.jhep.2010.11.004","volume":"54","author":"L McCormack","year":"2011","unstructured":"McCormack L, Dutkowski P, El-Badry AM, Clavien PA . 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