Pleiotropic Role of p53 in Injury and Liver Regeneration after Acetaminophen Overdose
Pleiotropic Role of p53 in Injury and Liver Regeneration after Acetaminophen Overdose
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DOI：
10.1016/j.ajpath.2018.03.006
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发表时间：
2018-06-01
影响因子：
6
通讯作者：
Apte, Udayan
中科院分区：
文献类型：
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作者：
Borude, Prachi;Bhushan, Bharat;Apte, Udayan
p53是参与增殖、细胞死亡、迁移和体内平衡的主要细胞看门人。p53在药物性肝损伤发病机制中的作用尚不清楚。我们研究了p53在对乙酰氨基酚（APAP）过量后肝损伤和再生中的作用，这是西方世界急性肝功能衰竭的最常见原因。用300 mg/kg APAP处理8周龄雄性野生型（WT）和p53敲除（p53 K 0）小鼠，并在0至96小时的时间过程中研究肝损伤和再生的动力学。p53缺失导致的肝损伤是WT小鼠的三倍。有趣的是，尽管肝损伤更高，但p53 K 0小鼠的恢复与WT小鼠相似，因为肝再生更快。p53的缺失不影响APAP的生物活化和损伤的起始。微阵列分析显示，p53 K 0小鼠破坏了代谢稳态，诱导了炎症和增殖信号。p53 K 0小鼠表现出与长期肝损伤相关的长期脂肪变性。p53 K 0小鼠肝再生的启动延迟，但一旦启动，细胞周期明显快于WT小鼠，因为持续的AKT，细胞外信号调节激酶，和哺乳动物雷帕霉素信号的靶点。这些研究表明，p53在APAP过量后发挥多效性作用，其中它通过维持代谢稳态来防止肝损伤的进展，并且还通过增殖信号传导来调节肝再生的启动。
p53 is the major cellular gatekeeper involved in proliferation, cell death, migration, and homeostasis. The role of p53 in pathogenesis of drug-induced liver injury is unknown. We investigated the role of p53 in liver injury and regeneration after acetaminophen (APAP) overdose, the most common cause of acute liver failure in the Western world. Eight-week-old male wild-type (WT) and p53 knockout (p53K0) mice were treated with 300 mg/kg APAP, and the dynamics of liver injury and regeneration were studied over a time course of 0 to 96 hours. Deletion of p53 resulted in a threefold higher liver injury than in WT mice. Interestingly, despite higher liver injury, p53K0 mice recovered similarly as the WT mice because of faster liver regeneration. Deletion of p53 did not affect APAP bioactivation and initiation of injury. Microarray analysis revealed that p53K0 mice had disrupted metabolic homeostasis and induced inflammatory and proliferative signaling. p53K0 mice showed prolonged steatosis correlating with prolonged liver injury. Initiation of liver regeneration in p53K0 mice was delayed, but once initiated, cell cycle was significantly faster than WT mice because of sustained AKT, extracellular signalregulated kinase, and mammalian target of rapamycin signaling. These studies show that p53 plays a pleotropic role after APAP overdose, where it prevents progression of liver injury by maintaining metabolic homeostasis and also regulates initiation of liver regeneration through proliferative signaling.