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Liver Specific Knockout Atg5 Causes Persistent Activation of Nrf2 and Protects Against Acetaminophen‐Induced Liver Injury
Author(s) -
Ding Wen-Xing,
Ni Hong-Min,
Apte Udayan,
Jaeschke Hartmut
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.396.3
Subject(s) - atg5 , autophagy , autophagosome , knockout mouse , liver injury , chemistry , acetaminophen , hepatocyte , glutathione , gene knockout , microbiology and biotechnology , biology , pharmacology , biochemistry , apoptosis , gene , enzyme , in vitro
Autophagy is a biological process which degrades intracellular proteins and organelles including damaged mitochondria through the formation of autophagosome. We previously demonstrated that pharmacological induction of autophagy protected against acetaminophen (APAP)‐induced liver injury. To our surprise, in the present study, we found that mice with the liver‐specific knockout of Atg5, an essential autophagy gene, were not more susceptible but rather more resistant to APAP‐induced liver injury. The lack of autophagy in the Atg5‐knockout mouse livers was confirmed by increased p62 protein levels and the absence of LC3‐lipidation as well as autophagosome formation. We also found that Nrf2, a transcriptional factor regulating drug detoxification and glutathione (GSH) synthesis gene expression, was persistently activated in the Atg5 knockout mouse livers. As a result, there were more unconjugated free hepatic GSH and less protein adducts formation in APAP‐treated Atg5 knockout mouse livers than in wild type mouse. In addition, we found that hepatocyte proliferation was significantly increased in Atg5 knockout mouse livers, which might also attenuate APAP‐induced liver injury by promoting liver regeneration. In conclusion, we found that persistent activation of Nrf2 and increased hepatocytes proliferation protected against APAP‐induced liver injury in Atg5‐liver specific knockout mice.