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Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice

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Title: Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice
Authors: Hui Qian, Qingyun Bai, Xiao Yang, Jephte Y. Akakpo, Lili Ji, Li Yang, Thomas Rülicke, Kurt Zatloukal, Hartmut Jaeschke, Hong-Min Ni, Wen-Xing Ding
Source: Acta Pharmaceutica Sinica B, Vol 11, Iss 12, Pp 3791-3805 (2021)
Publisher Information: Elsevier, 2021.
Publication Year: 2021
Collection: LCC:Therapeutics. Pharmacology
Subject Terms: Autophagy, Coagulation, DILI, Liver regeneration, Macrophage, Hepatotoxicity, Therapeutics. Pharmacology, RM1-950
More Details: Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2211-3835
Relation: http://www.sciencedirect.com/science/article/pii/S2211383521004421; https://doaj.org/toc/2211-3835
DOI: 10.1016/j.apsb.2021.11.010
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Accession Number: edsdoj.11c1a25a9fed4671869e8d06a1fde45d
Database: Directory of Open Access Journals
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  Data: Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice
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  Data: <searchLink fieldCode="AR" term="%22Hui+Qian%22">Hui Qian</searchLink><br /><searchLink fieldCode="AR" term="%22Qingyun+Bai%22">Qingyun Bai</searchLink><br /><searchLink fieldCode="AR" term="%22Xiao+Yang%22">Xiao Yang</searchLink><br /><searchLink fieldCode="AR" term="%22Jephte+Y%2E+Akakpo%22">Jephte Y. Akakpo</searchLink><br /><searchLink fieldCode="AR" term="%22Lili+Ji%22">Lili Ji</searchLink><br /><searchLink fieldCode="AR" term="%22Li+Yang%22">Li Yang</searchLink><br /><searchLink fieldCode="AR" term="%22Thomas+Rülicke%22">Thomas Rülicke</searchLink><br /><searchLink fieldCode="AR" term="%22Kurt+Zatloukal%22">Kurt Zatloukal</searchLink><br /><searchLink fieldCode="AR" term="%22Hartmut+Jaeschke%22">Hartmut Jaeschke</searchLink><br /><searchLink fieldCode="AR" term="%22Hong-Min+Ni%22">Hong-Min Ni</searchLink><br /><searchLink fieldCode="AR" term="%22Wen-Xing+Ding%22">Wen-Xing Ding</searchLink>
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  Data: Acta Pharmaceutica Sinica B, Vol 11, Iss 12, Pp 3791-3805 (2021)
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  Data: Elsevier, 2021.
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  Data: 2021
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  Data: LCC:Therapeutics. Pharmacology
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  Data: <searchLink fieldCode="DE" term="%22Autophagy%22">Autophagy</searchLink><br /><searchLink fieldCode="DE" term="%22Coagulation%22">Coagulation</searchLink><br /><searchLink fieldCode="DE" term="%22DILI%22">DILI</searchLink><br /><searchLink fieldCode="DE" term="%22Liver+regeneration%22">Liver regeneration</searchLink><br /><searchLink fieldCode="DE" term="%22Macrophage%22">Macrophage</searchLink><br /><searchLink fieldCode="DE" term="%22Hepatotoxicity%22">Hepatotoxicity</searchLink><br /><searchLink fieldCode="DE" term="%22Therapeutics%2E+Pharmacology%22">Therapeutics. Pharmacology</searchLink><br /><searchLink fieldCode="DE" term="%22RM1-950%22">RM1-950</searchLink>
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  Data: Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.
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