Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression
Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression
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DOI：
10.1096/fj.201901258rr
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发表时间：
2019-12-01
期刊：
影响因子：
4.8
通讯作者：
Chung, Hun Taeg
中科院分区：
文献类型：
--
作者：
Chen, Yingqing;Park, Hyeok-Jun;Chung, Hun Taeg
对乙酰氨基酚（APAP）被广泛用作推荐剂量的解热镇痛药物，而过量的APAP可导致严重的肝损伤。APAP诱导肝损伤的分子机制仍不完全清楚。一氧化碳（CO），血红素加氧酶（HO）-1活性的终产物，可以通过调节线粒体功能在细胞毒性模型中赋予抗炎和抗凋亡特性。本研究的目的是评估CO对APAP诱导的肝毒性的影响，以及CO与内质网（ER）应激和线粒体信号转导的调节的关系，使用CO释放分子或低浓度的CO作为预处理或后处理。分别在α小鼠肝细胞或原代肝细胞中使用基因缺失或敲低方法，我们研究了HO-1和线粒体自噬调节蛋白Parkin对APAP诱导的ER应激相关凋亡调节因子胞嘧啶-胞嘧啶-腺苷-胸苷（CCAAT）/增强子结合蛋白同源蛋白（CHOP）表达的作用。我们发现CO通过蛋白激酶RNA样ER激酶/真核翻译起始因子2-α/转录激活因子-4信号通路诱导肝细胞中Parkin的表达。此外，CO气体吸入显着减轻APAP诱导的肝损伤在体内，并相应地降低血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平以及促炎细胞因子，并减少CHOP在肝组织中的表达，同时显着增加肝HO-1和Parkin的表达。我们发现CO对APAP诱导的肝损伤的保护作用是通过分别诱导HO-1和Parkin在转录和翻译后水平下调CHOP介导的，并且与活性氧产生和JNK磷酸化的减少相关。我们的结论是，CO可能是一个有前途的治疗剂APAP诱导的肝损伤。
Acetaminophen (APAP) is widely used as an antifebrile and analgesic drug at recommended doses, whereas an overdose of APAP can cause severe liver damage. The molecular mechanisms underlying APAP-induced liver damage remain incompletely understood. Carbon monoxide (CO), an end-product of heme oxygenase (HO)-1 activity, can confer anti-inflammatory and antiapoptotic properties in cellular models of toxicity via regulation of mitochondrial function. The objective of this study was to evaluate the effects of CO on APAP-induced hepatotoxicity and CO's relationship to regulation of endoplasmic reticulum (ER) stress and mitochondrial signaling using CO-releasing molecules or low concentrations of CO applied as pretreatment or post-treatment. Using genetic deletion or knockdown approaches in alpha mouse liver cells or primary hepatocytes, respectively, we investigated the role of HO-1 and the mitophagy regulator protein Parkin on APAP-induced expression of the ER stress associated apoptosis regulator cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT)/enhancer-binding protein homologous protein (CHOP). We found that CO induced Parkin expression in hepatocytes via the protein kinase RNA-like ER kinase/eukaryotic translation initiation factor 2-alpha/activating transcription factor-4 signaling pathway. Additionally, CO gas inhalation significantly alleviated APAP-induced liver damage in vivo and correspondingly reduced serum alanine aminotransferase and aspartate aminotransferase levels as well as proinflammatory cytokines and reduced the expression of CHOP in liver tissues while dramatically increasing hepatic HO-1 and Parkin expression. We found that the protective effects of CO on APAP-induced liver damage were mediated by down-regulation of CHOP at a transcriptional and post-translational level via induction of HO-1 and Parkin, respectively, and associated with decreases in reactive oxygen species production and JNK phosphorylation. We conclude that CO may represent a promising therapeutic agent for APAP-induced liver injury.