Shen Xiyue, Ishaq Saddam Muhammad, Wang Qiao'e, Yuan Juntao, Gao Junling, Lu Zhongbing
College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
Key Laboratory of Cosmetic, China National Light Industry, Beijing Technology and Business University, Beijing 100048, China.
Antioxidants (Basel). 2022 Apr 29;11(5):880. doi: 10.3390/antiox11050880.
In many developed countries, acetaminophen (APAP) overdose-induced acute liver injury is a significant therapeutic problem. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a critical enzyme for asymmetric dimethylarginine (ADMA) metabolism. Growing evidence suggests that liver dysfunction is associated with increased plasma ADMA levels and reduced hepatic DDAH1 activity/expression. The purpose of this study was to investigate the involvement of DDAH1 in APAP-mediated hepatotoxicity using and DDAH1 transgenic mice. After APAP challenge, mice developed more severe liver injury than wild type (WT) mice, which was associated with a greater induction of fibrosis, oxidative stress, inflammation, cell apoptosis and phosphorylation of JNK. In contrast, overexpression of DDAH1 attenuated APAP-induced liver injury. RNA-seq analysis showed that DDAH1 affects xenobiotic metabolism and glutathione metabolism pathways in APAP-treated livers. Furthermore, we found that DDAH1 knockdown aggravated APAP-induced cell death, oxidative stress, phosphorylation of JNK and p65, upregulation of CYP2E1 and downregulation of GSTA1 in HepG2 cells. Collectively, our data suggested that DDAH1 has a marked protective effect against APAP-induced liver oxidative stress, inflammation and injury. Strategies to increase hepatic DDAH1 expression/activity may be novel approaches for drug-induced acute liver injury therapy.
在许多发达国家，对乙酰氨基酚（APAP）过量引起的急性肝损伤是一个重大的治疗难题。二甲基精氨酸二甲胺水解酶1（DDAH1）是不对称二甲基精氨酸（ADMA）代谢的关键酶。越来越多的证据表明，肝功能障碍与血浆ADMA水平升高及肝脏DDAH1活性/表达降低有关。本研究的目的是使用[具体内容缺失]和DDAH1转基因小鼠来研究DDAH1在APAP介导的肝毒性中的作用。APAP攻击后，[具体内容缺失]小鼠比野生型（WT）小鼠发生更严重的肝损伤，这与更大程度的纤维化、氧化应激、炎症、细胞凋亡诱导以及JNK磷酸化有关。相反，DDAH1的过表达减轻了APAP诱导的肝损伤。RNA测序分析表明，DDAH1影响APAP处理的肝脏中的外源性物质代谢和谷胱甘肽代谢途径。此外，我们发现，在HepG2细胞中，DDAH1基因敲低加重了APAP诱导的细胞死亡、氧化应激、JNK和p65磷酸化、CYP2E1上调以及GSTA1下调。总体而言，我们的数据表明，DDAH1对APAP诱导的肝脏氧化应激、炎症和损伤具有显著的保护作用。增加肝脏DDAH1表达/活性的策略可能是药物性急性肝损伤治疗的新方法。
