title: p62/SQSTM1 plays a protective role in oxidative injury of steatotic liver in a mouse hepatectomy model.
abstract: OBJECTIVE
  Liver injury and regeneration involve complicated processes and are affected by various physio-pathological factors. We investigated the mechanisms of steatosis-associated liver injury and delayed regeneration in a mouse model of partial hepatectomy.
  
  
  RESULTS
  Initial regeneration of the steatotic liver was significantly delayed after hepatectomy. Although hepatocyte proliferation was not significantly suppressed, severe liver injury with oxidative stress (OS) occurred immediately after hepatectomy in the steatotic liver. Fas-ligand (FasL)/Fas expression was upregulated in the steatotic liver, whereas the expression of antioxidant and anti-apoptotic molecules (catalase/MnSOD/Ref-1 and Bcl-2/Bcl-xL/FLIP, respectively) and p62/SQSTM1, a steatosis-associated protein, was downregulated. Interestingly, pro-survival Akt was not activated in response to hepatectomy, although it was sufficiently expressed even before hepatectomy. Suppression of p62/SQSTM1 increased FasL/Fas expression and reduced nuclear factor erythroid 2-related factor-2 (Nrf-2)-dependent antioxidant response elements activity and antioxidant responses in steatotic and nonsteatotic hepatocytes. Exogenously added FasL induced severe cellular OS and necrosis/apoptosis in steatotic hepatocytes, with only the necrosis being inhibited by pretreatment with antioxidants, suggesting that FasL/Fas-induced OS mainly leads to necrosis. Furthermore, p62/SQSTM1 re-expression in the steatotic liver markedly reduced liver injury and improved liver regeneration.
  
  
  METHODS
  This study is the first which demonstrates that reduced expression of p62/SQSTM1 plays a crucial role in posthepatectomy acute injury and delayed regeneration of steatotic liver, mainly via redox-dependent mechanisms.
  
  
  CONCLUSIONS
  In the steatotic liver, reduced expression of p62/SQSTM1 induced FasL/Fas overexpression and suppressed antioxidant genes, mainly through Nrf-2 inactivation, which, along with the hypo-responsiveness of Akt, caused posthepatectomy necrotic/apoptotic liver injury and delayed regeneration, both mainly via a redox-dependent mechanism.
authors.affiliation: 1 Laboratory of Molecular and Functional Bio-imaging, Faculty of Health Sciences, Hokkaido University , Sapporo, Japan .
authors.forename: Sanae
authors.initials: S
authors.lastname: Haga
authors.forename: Takeaki
authors.initials: T
authors.lastname: Ozawa
authors.forename: Yuma
authors.initials: Y
authors.lastname: Yamada
authors.forename: Naoki
authors.initials: N
authors.lastname: Morita
authors.forename: Izuru
authors.initials: I
authors.lastname: Nagashima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Natsumi
authors.initials: N
authors.lastname: Noda
authors.forename: Riichiro
authors.initials: R
authors.lastname: Abe
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000096:biosynthesis; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D006498:Hepatectomy; D022781:Hepatocytes / Q000378:metabolism; D008115:Liver Regeneration / Q000235:genetics; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006360:Heat-Shock Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse