Loss of autophagy promotes murine acetaminophen hepatotoxicity
Loss of autophagy promotes murine acetaminophen hepatotoxicity
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DOI：
10.1007/s00535-011-0500-0
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发表时间：
2012-04-01
影响因子：
6.3
通讯作者：
Watanabe, Sumio
中科院分区：
文献类型：
--
作者：
Igusa, Yuki;Yamashina, Shunhei;Watanabe, Sumio
以往的报道表明，线粒体功能障碍在扑热息痛所致肝损伤的发生发展中起重要作用。另一方面，自噬是一种主要的分解代谢途径，在清除蛋白质聚集体以及破坏或过剩线粒体以维持细胞内平衡方面发挥着关键作用。本研究的目的是阐明自噬是否与对乙酰氨基酚引起的肝损伤有关。对乙酰氨基酚被给予肝脏特异性ATG7缺陷小鼠和野生型小鼠的腹膜内注射。用多种细胞和分子方法评价自噬在扑热息痛诱导的细胞死亡中的作用。扑热息痛治疗可诱导野生型小鼠肝细胞中自噬小体的形成，但在ATG7缺陷小鼠中不能。自噬缺陷增加了扑热息痛诱导的肝损伤和肝脏中caspase-3和-7的激活。自噬缺陷可加速扑热息痛诱导的肝细胞ROS生成、线粒体膜去极化和JNK活性。环孢菌素A或JNK抑制剂(SP600125)与对乙酰氨基酚联合使用可抑制对乙酰氨基酚诱导的自噬缺陷肝细胞的凋亡和坏死性细胞死亡。在对乙酰氨基酚治疗过程中诱导自噬，通过清除受损的线粒体和氧化应激，在保护对乙酰氨基酚诱导的肝毒性中起着关键作用。
Previous reports indicate that mitochondrial dysfunction is essential for the development of liver injury due to acetaminophen. On the other hand, autophagy, which is a major catabolic pathway, plays a critical role in removing protein aggregates, as well as damaged or excess mitochondria in order to maintain intracellular homeostasis. The aim of this study was to clarify if autophagy is linked to liver injury due to acetaminophen.Acetaminophen was administered intraperitoneally to liver-specific Atg7-deficient mice and wild-type mice. A variety of cellular and molecular approaches were used to evaluate the role of autophagy in acetaminophen-induced cell death.Treatment with acetaminophen induced formation of autophagosomes in hepatocytes from wild-type mice, but not in Atg7-deficient mice. Autophagy deficiency enhanced acetaminophen-induced liver injury and activation of caspase-3 and -7 in the liver. Acetaminophen-induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, and JNK activation in hepatocytes were accelerated by autophagy deficiency. The combination of cyclosporin A or JNK inhibitor (SP600125) with acetaminophen blunted both acetaminophen-induced apoptotic and necrotic cell death in autophagy-deficient hepatocytes.Induction of autophagy during acetaminophen treatment plays a pivotal role in the protection against acetaminophen-induced hepatotoxicity through the removal of damaged mitochondria and oxidative stress.