p62/SQSTM1 Plays a Protective Role in Oxidative Injury of Steatotic Liver in a Mouse Hepatectomy Model

Haga Sanae; Ozawa Takeaki; Yamada Yuma; Morita Naoki; Nagashima Izuru; Inoue Hiroshi; Inaba Yuka; Noda Natsumi; Abe Riichiro; Umezawa Kazuo; Ozaki Michitaka

Title	en p62/SQSTM1 Plays a Protective Role in Oxidative Injury of Steatotic Liver in a Mouse Hepatectomy Model
Creator	en Haga, Sanae NRID 1000060706505 en Ozawa, Takeaki en Yamada, Yuma NRID 1000060451431 en Morita, Naoki en Nagashima, Izuru en Inoue, Hiroshi en Inaba, Yuka en Noda, Natsumi en Abe, Riichiro NRID 1000060344511 en Umezawa, Kazuo NRID 1000070114402 en Ozaki, Michitaka NRID 1000080256510
Accessrights	open access
Rights	en The final published version is available from Mary Ann Liebert, Inc., publishers at http://dx.doi.org/10.1089/ars.2013.5391
Description	Abstract en Aims: 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. Innovation: 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. Conclusion: 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. Antioxid. Redox Signal. 21, 2515-2530.
Publisher	en Mary Ann Liebert
Date	Issued2014-12-20
Language	eng
Resource Type	journal article
Version Type	AM
Identifier	HDL http://hdl.handle.net/2115/60349
Relation	isVersionOf DOI https://doi.org/10.1089/ars.2013.5391 PMID 24925527
Journal	PISSN 1523-0864 NCID AA11507484 en Antioxidants & redox signaling Volume Number21 Issue Number18 Page Start2515 Page End2530
File	fulltext Antioxid Redox Signal_21(18)_2515-2530.pdf 2.91 MB (application/pdf) Issued2014-12-20
Oaidate	2023-07-26