Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice
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 incr...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-12-01
|
| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383521004421 |
| _version_ | 1819229481387163648 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Hui Qian |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T11:13:52Z |
| format | Article |
| id | doaj.art-11c1a25a9fed4671869e8d06a1fde45d |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-23T11:13:52Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-11c1a25a9fed4671869e8d06a1fde45d2022-12-21T17:49:15ZengElsevierActa Pharmaceutica Sinica B2211-38352021-12-01111237913805Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in miceHui Qian0Qingyun Bai1Xiao Yang2Jephte Y. Akakpo3Lili Ji4Li Yang5Thomas Rülicke6Kurt Zatloukal7Hartmut Jaeschke8Hong-Min Ni9Wen-Xing Ding10Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA; The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; School of Chemistry and Bioengineering, Yichun University, Yichun 336000, ChinaDepartment of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA; The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaDepartment of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USAThe MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaThe MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaDepartment of Biomedical Sciences, University of Veterinary Medicine Vienna Veterinärplatz, Vienna 1210, AustriaThe Institute of Pathology, Medical University of Graz, Graz A-8036, AustriaDepartment of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USADepartment of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA; Corresponding author. Tel.: +1 913 588 9813; fax: +1 913 588 7501.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.http://www.sciencedirect.com/science/article/pii/S2211383521004421AutophagyCoagulationDILILiver regenerationMacrophageHepatotoxicity |
| spellingShingle | 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 Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice Acta Pharmaceutica Sinica B Autophagy Coagulation DILI Liver regeneration Macrophage Hepatotoxicity |
| title | Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice |
| title_full | Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice |
| title_fullStr | Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice |
| title_full_unstemmed | Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice |
| title_short | Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice |
| title_sort | dual roles of p62 sqstm1 in the injury and recovery phases of acetaminophen induced liver injury in mice |
| topic | Autophagy Coagulation DILI Liver regeneration Macrophage Hepatotoxicity |
| url | http://www.sciencedirect.com/science/article/pii/S2211383521004421 |
| work_keys_str_mv | AT huiqian dualrolesofp62sqstm1intheinjuryandrecoveryphasesofacetaminopheninducedliverinjuryinmice AT qingyunbai dualrolesofp62sqstm1intheinjuryandrecoveryphasesofacetaminopheninducedliverinjuryinmice AT xiaoyang dualrolesofp62sqstm1intheinjuryandrecoveryphasesofacetaminopheninducedliverinjuryinmice AT jephteyakakpo dualrolesofp62sqstm1intheinjuryandrecoveryphasesofacetaminopheninducedliverinjuryinmice AT liliji dualrolesofp62sqstm1intheinjuryandrecoveryphasesofacetaminopheninducedliverinjuryinmice AT liyang dualrolesofp62sqstm1intheinjuryandrecoveryphasesofacetaminopheninducedliverinjuryinmice AT thomasrulicke dualrolesofp62sqstm1intheinjuryandrecoveryphasesofacetaminopheninducedliverinjuryinmice AT kurtzatloukal dualrolesofp62sqstm1intheinjuryandrecoveryphasesofacetaminopheninducedliverinjuryinmice AT hartmutjaeschke dualrolesofp62sqstm1intheinjuryandrecoveryphasesofacetaminopheninducedliverinjuryinmice AT hongminni dualrolesofp62sqstm1intheinjuryandrecoveryphasesofacetaminopheninducedliverinjuryinmice AT wenxingding dualrolesofp62sqstm1intheinjuryandrecoveryphasesofacetaminopheninducedliverinjuryinmice |