Acetaminophen Responsive miR-19b Modulates SIRT1/Nrf2 Signaling Pathway in Drug-Induced Hepatotoxicity
Acetaminophen Responsive miR-19b Modulates SIRT1/Nrf2 Signaling Pathway in Drug-Induced Hepatotoxicity
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对乙酰氨基酚响应性 miR-19b 调节药物引起的肝毒性中的 SIRT1/Nrf2 信号通路
DOI：
10.1093/toxsci/kfz095
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发表时间：
2019
影响因子：
3.8
通讯作者：
Weifeng Huang
中科院分区：
文献类型：
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作者：
Xing Liu;Hongqian Zhao;Chunyan Luo;Debin Du;Jinlong Huang;Quan Ming;Fen Jin;Decheng Wang;Weifeng Huang
先前的研究表明，SIRT 1的激活保护肝脏免受对乙酰氨基酚（APAP）诱导的损伤;然而，SIRT 1在这一过程中的调节的详细机制仍然不完整。因此，本研究旨在探讨SIRT 1在APAP介导的肝毒性中的病理生理作用。我们发现，APAP暴露后，人LO 2细胞和小鼠肝脏中SIRT 1 mRNA和蛋白表达显著上调，SIRT 1表达的特异性下调最终加重了APAP诱导的LO 2细胞抗氧化防御。此外，慢病毒介导的肝脏SIRT 1表达的敲低加剧了APAP诱导的氧化应激和肝损伤，特别是Nrf 2的减少和随后的几个抗氧化基因的下调。有趣的是，30 mg/kg SRT 1720，特异性SIRT 1激活剂，大大增强了Nrf 2表达和抗氧化防御，然后最终逆转了APAP诱导的小鼠肝脏损伤。此外，APAP反应性miR-19 b在调节SIRT 1表达中起重要作用，而过表达miR-19 b在很大程度上消除了APAP在体外和体内对SIRT 1的诱导作用。特异性SIRT 1 3′-UTR突变，破坏了miRNA-3′UTR的相互作用，并成功消除了miR-19 b的调节作用。值得注意的是，肝脏miR-19 b过表达加重了APAP诱导的肝毒性。总的来说，我们的研究结果支持这样的观点，即APAP响应性miR-19 b强烈升高SIRT 1可能代表了一种补偿机制，以保护肝脏免受药物诱导的损伤，至少部分通过增强肝脏中Nrf 2介导的抗氧化能力。
Previous studies suggest that activation of SIRT1 protects liver from acetaminophen (APAP)-induced injury; however, the detailed mechanism of SIRT1 modulation in this process is still incomplete. Therefore, this study was to investigate the pathophysiological role of SIRT1 in APAP-mediated hepatotoxicity. We found that SIRT1 mRNA and protein were markedly upregulated in human LO2 cells and mouse liver upon APAP exposure.In vitro, the specific knockdown of SIRT1 expression ultimately aggravated APAP-evoked cellular antioxidant defense in LO2 cells. Moreover, lentivirus-mediated knockdown of hepatic SIRT1 expression exacerbated APAP-induced oxidative stress and liver injury, especially reduction of Nrf2 and subsequent downregulation of several antioxidant genes. Intriguingly, 30 mg/kg SRT1720, the specific SIRT1 activator, which greatly enhanced Nrf2 expression and antioxidant defense, and then eventually reversed APAP-induced hepatic liver injury in mice. Furthermore, APAP responsive miR-19b played an important role in regulating SIRT1 expression, whereas overexpression miR-19b largely abolished the induction of SIRT1 by APAPin vitroandin vivo. Specific SIRT1 3′-UTR mutation, which disrupted the interaction of miRNA-3′UTR, and successfully abrogated the modulation by miR-19b. Notably, hepatic miR-19b overexpression worsened the APAP-induced hepatotoxicity. In general, our results support the notion that the strong elevation of SIRT1 by APAP responsive miR-19b may represent a compensatory mechanism to protect liver against the drug-induced damage, at least in part by enhancing Nrf2-mediated antioxidant capacity in the liver.