Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice.
Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice.
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DOI：
10.1016/j.apsb.2021.11.010
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Ding WX
中科院分区：
文献类型：
--
作者：
Qian H;Bai Q;Yang X;Akakpo JY;Ji L;Yang L;Rülicke T;Zatloukal K;Jaeschke H;Ni HM;Ding WX
对乙酰氨基酚（APAP）过量可引起肝损伤，是美国急性肝功能衰竭的最常见原因。我们研究了p62/SQSTM 1（简称p62）在APAP诱导的小鼠肝损伤（AILI）中的作用。我们发现，肝脏蛋白水平的p62显着增加，在24小时后，APAP处理，这是负相关的APAP加合物的肝脏水平。APAP还在24小时激活mTOR，这与增加的细胞增殖相关。相比之下，p62敲除（KO）小鼠表现出增加的APAP-加合物的肝脏水平检测到的特异性抗体使用蛋白质印迹分析，但减少mTOR的激活和细胞增殖与APAP治疗后24小时加重肝损伤。令人惊讶的是，p62 KO小鼠从AILI中恢复，而野生型小鼠在48 h时仍持续肝损伤。我们发现p62 KO小鼠中浸润的巨噬细胞数量增加，伴有肝血管性血友病因子（VWF）和血小板聚集减少，这与APAP治疗后48 h细胞增殖增加和肝损伤改善有关。我们的数据表明，p62通过增加APAP加合物和线粒体的自噬选择性清除来抑制AILI的晚期损伤阶段，但可能通过增强肝脏血液凝固来损害AILI的恢复阶段。p62通过增加对乙酰氨基酚加合物和线粒体的自噬选择性清除来抑制对乙酰氨基酚诱导的肝损伤（AILI）的晚期损伤阶段，但可能通过增强肝凝血来损害AILI的恢复阶段。
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. p62 inhibits the late injury phase of acetaminophen-induced liver injury (AILI) by increasing autophagic selective removal of acetaminophen-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.
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4-甲基吡唑可预防小鼠和原发性肝细胞中的对乙酰氨基酚肝毒性。
影响因子：
2.8
作者：
Akakpo JY;Ramachandran A;Kandel SE;Ni HM;Kumer SC;Rumack BH;Jaeschke H
通讯作者：
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DOI：
10.1056/nejmct0708278
发表时间：
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期刊：
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影响因子：
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影响因子：
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作者：
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影响因子：
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