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

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

Haga, Sanae; Ozawa, Takeaki; Yamada, Yuma et al.

Antioxidants & redox signaling, 2014, 21(18), 2515-2530

Permalink : https://hdl.handle.net/2115/60349

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アクセス権	open access
URI	https://hdl.handle.net/2115/60349
タイトル	p62/SQSTM1 Plays a Protective Role in Oxidative Injury of Steatotic Liver in a Mouse Hepatectomy Model
著者	Haga, Sanae ; Ozawa, Takeaki ; Yamada, Yuma ; Morita, Naoki ; Nagashima, Izuru ; Inoue, Hiroshi ; Inaba, Yuka ; Noda, Natsumi ; Abe, Riichiro ; Umezawa, Kazuo ; Ozaki, Michitaka
e-Rad_Researcher 60706505 著者名 Haga, Sanae
著者名 Ozawa, Takeaki
e-Rad_Researcher 60451431 著者名 Yamada, Yuma
著者名 Morita, Naoki
著者名 Nagashima, Izuru
著者名 Inoue, Hiroshi
著者名 Inaba, Yuka
著者名 Noda, Natsumi
e-Rad_Researcher 60344511 著者名 Abe, Riichiro
e-Rad_Researcher 70114402 著者名 Umezawa, Kazuo
e-Rad_Researcher 80256510 著者名 Ozaki, Michitaka
言語	英語
発行日	2014-12-20
出版者	Mary Ann Liebert
収録物名	Antioxidants & redox signaling
巻(号)	21(18)
ページ	2515-2530
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	The final published version is available from Mary Ann Liebert, Inc., publishers at http://dx.doi.org/10.1089/ars.2013.5391
PISSN	1523-0864
NCID	AA11507484
関連情報	PMID 24925527
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1089/ars.2013.5391