Mannan-binding lectin attenuates acetaminophen-induced hepatotoxicity by regulating CYP2E1 expression via ROS-dependent JNK/SP1 pathway
Mannan-binding lectin attenuates acetaminophen-induced hepatotoxicity by regulating CYP2E1 expression via ROS-dependent JNK/SP1 pathway
复制标题
甘露聚糖结合凝集素通过 ROS 依赖性 JNK/SP1 途径调节 CYP2E1 表达，减轻对乙酰氨基酚诱导的肝毒性
DOI：
10.1002/eji.201847830
复制
发表时间：
2019
影响因子：
5.4
通讯作者：
Zuo Daming
中科院分区：
文献类型：
--
作者：
Li Huifang;Liu Yan;Li Junru;Liu Yunzhi;Dong Lijun;Yin Yue;Yu Yu;Zhou Jia;Zhang Liyun;Lu Xiao;Chen Zhengliang;Zuo Daming
甘露聚糖结合凝集素（MBL）作为先天免疫系统中的可溶性模式识别分子，主要由肝脏产生。MBL缺乏症在人群中发生的频率很高，据报道与几种肝脏疾病的易感性有关。在本研究中，我们研究了MBL在对乙酰氨基酚（APAP）诱导的肝毒性中的病理生理作用。APAP治疗后，MBL-缺陷（MBL-/-）小鼠的死亡率显著高于对照小鼠，肝坏死加重，血清乳酸脱氢酶和丙氨酸转氨酶水平升高。MBL−/−小鼠的肝毒性增强与APAP毒性代谢物浓度增加有关。此外，我们在这里证明，MBL的基因消融导致过量的活性氧（ROS）产生和增强的c-Jun N-末端激酶（JNK）激活，导致特异性蛋白1（SP1）核表达上调，从而促进CYP 2 E1肝脏表达，从而加剧APAP诱导的小鼠肝损伤。重要的是，我们已经验证了MBL以相同的机制在体外保护人HepaRG细胞免受APAP毒性。我们的研究揭示了MBL在药物代谢中的意想不到的功能，从而为MBL缺乏症患者的药物性肝损伤提供了新的见解。
Mannan‐binding lectin (MBL) acts as a soluble pattern recognition molecule in the innate immune system, which is primarily produced by the liver. MBL deficiency occurs with high frequency in the population and is reported to be associated with susceptibility to several liver diseases. In the present study, we investigated the pathophysiological role of MBL in acetaminophen (APAP)‐induced hepatotoxicity. After APAP treatment, MBL‐deficient (MBL−/−) mice had significantly higher mortality and aggravated hepatic necrosis as well as elevated serum lactate dehydrogenase and alanine aminotransferase levels compared to control mice. The enhanced hepatotoxicity in MBL−/−mice was associated with increased concentration of APAP toxic metabolisms. Furthermore, we demonstrated here that genetic ablation of MBL resulted in excessive reactive oxygen species (ROS) production and enhanced c‐Jun N‐terminal kinase (JNK) activation, leading to up‐regulated specificity protein 1 (SP1) nuclear expression, thus promoted CYP2E1 hepatic expression and consequently exacerbated APAP‐induced liver injury in mice. Importantly, we have validated that MBL protected against APAP toxicity in human HepaRG cells in vitro with the same mechanism. Our study revealed an unexpected function of MBL in drug metabolism, thus providing new insight into the drug‐induced liver injury in patients with MBL deficiency.