Natural Polyphenol Chlorogenic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Activating ERK/Nrf2 Antioxidative Pathway
Natural Polyphenol Chlorogenic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Activating ERK/Nrf2 Antioxidative Pathway
复制标题
天然多酚绿原酸通过激活 ERK/Nrf2 抗氧化途径预防对乙酰氨基酚诱导的肝毒性
DOI：
10.1093/toxsci/kfx230
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发表时间：
2018-03-01
影响因子：
3.8
通讯作者：
Ji, Lili
中科院分区：
文献类型：
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作者：
Wei, Mengjuan;Zheng, Zhiyong;Ji, Lili
对乙酰氨基酚（acetaminophen，APAP）过量引起的肝毒性是临床上药物性急性肝衰竭的主要原因。绿原酸（CGA），一种膳食多酚，在我们以前的研究中被报道可以预防APAP诱导的肝损伤。本研究旨在通过关注核因子红细胞2相关因子2（Nrf 2）和细胞外调节蛋白激酶（ERK）1/2来研究CGA对APAP诱导的肝毒性的保护作用。CGA防止APAP诱导的氧化性肝损伤，并增强小鼠和肝细胞中Nrf 2的体外活化。在体外应用Nrf 2 siRNA和在体内应用Nrf 2敲除小鼠后，CGA提供的对APAP诱导的肝毒性的保护作用减弱。CGA增强血红素加氧酶-1（HO-1）和NAD（P）H：醌氧化还原酶-1（NQO 1）的表达，其抑制剂降低CGA对APAP诱导的肝细胞毒性的保护作用。分子对接结果表明，CGA与Kelch-like ECH相关蛋白1（Keap 1）中的Nrf 2结合位点可能存在相互作用。CGA可降低PP 2A亚基A（PP 2A-A）和PP 5等蛋白磷酸酶的表达，并诱导ERK 1/2持续磷酸化。此外，ERK 1/2抑制剂（U 0126和PD 98059）和ERK 2 siRNA废除了CGA诱导的Nrf 2磷酸化及其随后的转录激活，也减少了CGA对APAP诱导的肝细胞毒性的保护作用。这些结果表明，CGA通过阻断Nrf 2与其抑制蛋白Keap 1的结合，激活Nrf 2抗氧化信号通路，从而保护APAP诱导的肝毒性，ERK 1/2在调节CGA诱导的Nrf 2转录激活中起关键作用。CGA是一种很有前途的治疗药物，用于解毒APAP诱导的肝毒性。
Hepatotoxicity due to acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure in clinic. Chlorogenic acid (CGA), a dietary polyphenol, was reported to prevent APAP-induced liver injury in our previous studies. This study aims to investigate the protection provided by CGA against APAP-induced hepatotoxicity via focusing on nuclear factor erythroid 2-related factor 2 (Nrf2) and extracellular regulated protein kinases (ERK) 1/2. CGA prevented APAP-induced oxidative liver injury and enhanced Nrf2 activation in mice and in hepatocytes in vitro. CGA-provided the protection against APAP-induced hepatotoxicity was diminished after the application of Nrf2 siRNA in vitro and Nrf2 knockout mice in vivo. CGA enhanced the expression of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1), and their inhibitors reduced the protection provided by CGA against APAP-induced cytotoxicity in hepatocytes. Molecular docking results indicated the potential interaction of CGA with Nrf2 binding site in Kelch-like ECH-associating protein-1 (Keap1). CGA decreased the expression of protein phosphatases including PP2A subunit A (PP2A-A) and PP5, and induced the sustained ERK1/2 phosphorylation. Moreover, ERK1/2 inhibitors (U0126 and PD98059) and ERK2 siRNA abrogated CGA-induced Nrf2 phosphorylation and its subsequent transcriptional activation, and also reduced the protection provided by CGA against APAP-induced cytotoxicity in hepatocytes. These results suggest that CGA protects against APAP-induced hepatotoxicity by activating Nrf2 antioxidative signaling pathway via blocking the binding of Nrf2 to its inhibitor protein Keap1, and ERK1/2 plays a critical role in regulating CGA-induced Nrf2 transcriptional activation. CGA is a promising therapeutic agent for the detoxification of APAP-induced hepatotoxicity.