Zuo Chao, Sun Dong-Lei, Zhao Tian-He, Wang Jing-Jing, Zhang Zun-Zhen
Department of Occupational Health and Environmental Hygiene,West China School of Public Health and West China Fourth Hospital,Sichuan University,Chengdu 610041,China.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2022 Apr;44(2):253-261. doi: 10.3881/j.issn.1000-503X.14189.
Objective To explore the potential targets of triclosan in the treatment of nonalcoholic fatty liver disease(NAFLD) and to provide new clues for the future research on the application of triclosan. Methods The targets of triclosan and NAFLD were obtained via network pharmacology.The protein-protein interaction network was constructed with the common targets shared by triclosan and NAFLD.The affinity of triclosan to targets was verified through molecular docking.Gene ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment were carried out to analyze the key targets and the potential mechanism of action.NAFLD model was established by feeding male C57BL/6J mice with high-fat diet for 12 weeks.The mice were randomly assigned into a model group and a triclosan group [400 mg/(kg·d),gavage once a day for 8 weeks].The hematoxylin-eosin(HE) staining was used for observation of the pathological changes and oil red O staining for observation of fat deposition in mouse liver.Western blotting was employed to detect the protein level of peroxisome proliferator-activated receptor alpha(PPARα) in the liver tissue. Results Triclosan and NAFLD had 34 common targets,19 of which may be the potential targets for the treatment,including albumin(ALB),PPARα,mitogen-activated protein kinase 8(MAPK8),and fatty acid synthase.Molecular docking predicted that ALB,PPARα,and MAPK8 had good binding ability to triclosan.KEGG pathway enrichment showcased that the targets were mainly enriched in peroxisome proliferator-activated receptor signaling pathway,in which ALB and MAPK8 were not involved.Triclosan alleviated the balloon-like change and lipid droplet vacuole,decreased the lipid droplet area,and up-regulated the expression level of PPARα in mouse liver tissue. Conclusion PPARα is a key target of triclosan in the treatment of NAFLD,which may be involved in fatty acid oxidation through the peroxisome proliferator activated receptor signaling pathway.
目的 探讨三氯生治疗非酒精性脂肪性肝病（NAFLD）的潜在靶点，为三氯生应用的未来研究提供新线索。方法 通过网络药理学获取三氯生和NAFLD的靶点。用三氯生和NAFLD共有的共同靶点构建蛋白质-蛋白质相互作用网络。通过分子对接验证三氯生与靶点的亲和力。进行基因本体（GO）注释和京都基因与基因组百科全书（KEGG）通路富集分析关键靶点及潜在作用机制。通过给雄性C57BL/6J小鼠喂食高脂饮食12周建立NAFLD模型。将小鼠随机分为模型组和三氯生组[400 mg/(kg·d)，每天灌胃1次，共8周]。采用苏木精-伊红（HE）染色观察病理变化，油红O染色观察小鼠肝脏脂肪沉积情况。采用蛋白质印迹法检测肝组织中过氧化物酶体增殖物激活受体α（PPARα）的蛋白水平。结果 三氯生和NAFLD有34个共同靶点，其中19个可能是治疗的潜在靶点，包括白蛋白（ALB）、PPARα、丝裂原活化蛋白激酶8（MAPK8）和脂肪酸合酶。分子对接预测ALB、PPARα和MAPK8与三氯生具有良好的结合能力。KEGG通路富集显示靶点主要富集在过氧化物酶体增殖物激活受体信号通路，其中ALB和MAPK8未参与。三氯生减轻了小鼠肝组织中的气球样变和脂滴空泡，降低了脂滴面积，并上调了PPARα的表达水平。结论 PPARα是三氯生治疗NAFLD的关键靶点，其可能通过过氧化物酶体增殖物激活受体信号通路参与脂肪酸氧化。
