DDX3X肝特异性敲除在对乙酰氨基酚诱导小鼠急性肝损伤中的作用机制研究  

Mechanistic research on DDX3X hepatocyte specific knockout in acetaminopheninduced acute liver injury in mice

作　　者：莫胤康 范子豪 徐玲 任锋[1] MO Yinkang;FAN Zihao;XU Ling;REN Feng(Beijing Institute of Hepatology,Beijing YouAn Hospital,Capital Medical University,Beijing 100069,China)

机构地区：[1]首都医科大学附属北京佑安医院/北京肝病研究所,北京100069

出　　处：《胃肠病学和肝病学杂志》2025年第4期554-559,共6页Chinese Journal of Gastroenterology and Hepatology

基　　金：国家自然科学基金(81770611,82002243);北京自然科学基金和北京市教委联合资助重点项目(KZ202010025035);首都卫生发展科研专项重点攻关项目(SF2020-1-1151);北京市科技计划“首都临床诊疗技术研究及示范应用”专项课(Z191100006619096,Z191100006619097);北京市医院管理中心“青苗”计划专项经费资助项目(QML20201702);北京市医管局“登峰”人才计划(DFL20221503);高层次公共卫生技术人才建设项目(学科带头人-02-13);2023年度北京市自然科学基金-昌平创新联合基金拟资助项目(L234046)。

摘　　要：目的探讨DDX3X在对乙酰氨基酚(acetaminophen,APAP)诱导小鼠急性肝损伤(APAP-induced acute liver injury,AILI)中的作用及机制。方法动物实验使用C57BL/6J小鼠(包括野生型、DDX3X^(fl/fl)和DDX3X^(Δhep)小鼠),APAP(300 mg/kg)诱导急性肝损伤。检测肝功、病理评价小鼠肝脏损伤;qRT-PCR方法检测基因表达水平;利用Western blotting方法确定蛋白表达含量;ELISA方法鉴定小鼠血清中蛋白表达水平。结果DDX3X的基因和蛋白表达在APAP处理时间梯度中先上升后降低;APAP处理24 h后,DDX3X^(fl/fl)小鼠出现了严重的肝损伤,而DDX3X^(Δhep)小鼠的肝损伤显著减轻,主要表现在小鼠肝功水平显著降低(P<0.05),病理坏死区域和炎症细胞浸润面积减少。两组小鼠中肝组织CYP2E1和GSH的蛋白表达在两组间差异无统计学意义(P>0.05)。同时,与DDX3X^(fl/fl)小鼠相比,DDX3X^(Δhep)小鼠在APAP处理后炎症指标TNF-α、IL-1β和IL-6在肝组织中基因表达和血清中含量均显著降低(P<0.05)。结论DDX3X肝特异性敲除可能通过降低炎症反应来明显改善小鼠AILI,这为DDX3X在调控肝损伤的功能方面提供了理论支撑。Objective To explore the role and mechanism of DDX3X in APAP-induced acute liver injury(AILI)model in mice.Methods Animal experiments were performed using C57BL/6J mice(including wild-type,DDX3X ^(fl/fl) and DDX3X^(Δhep) mice).Acute liver injury was induced by APAP(300 mg/kg).Liver function and histopathology were assessed to evaluate liver damage.Gene expression levels were measured by qRT-PCR,protein expression levels were determined by Western blotting,and serum protein levels were analyzed using ELISA.Results The expression of DDX3X at both the gene and protein levels initially increased and then decreased in response to APAP treatment over time.At 24 hours post-APAP treatment,DDX3X ^(fl/fl) mice exhibited severe liver injury,while liver injury in DDX3X^(Δhep) mice was significantly alleviated,as evidenced by significantly improved liver function(P<0.05),reduced necrotic regions,and decreased inflammatory cell infiltration.No statistical differences were observed between the two groups in the protein expression levels of CYP2E1 and GSH(P>0.05).Moreover,compared to DDX3X^( fl/fl) mice,DDX3X^(Δhep) mice showed significantly reduced gene expression and serum levels of inflammatory markers TNF-α,IL-1β,and IL-6 after APAP treatment(P<0.05).Conclusion DDX3X hepatocyte specific knockout may significantly improve AILI in mice by reducing inflammatory response,providing theoretical support for the function of DDX3X in regulating liver injury.

关 键 词：对乙酰氨基酚 药物性肝损伤 DDX3X 炎症反应 

分 类 号：R575[医药卫生—消化系统]