Integrative proteomics-metabolomics strategy reveals the mechanism of hepatotoxicity induced by Fructus Psoraleae
Integrative proteomics-metabolomics strategy reveals the mechanism of hepatotoxicity induced by Fructus Psoraleae
复制标题
蛋白质组学-代谢组学一体化策略揭示补骨脂肝毒性机制
DOI：
10.1016/j.jprot.2020.103767
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发表时间：
2020-06-15
影响因子：
3.3
通讯作者：
Li, Yubo
中科院分区：
文献类型：
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作者：
Duan, Jingyi;Dong, Wenying;Li, Yubo
枸杞子（Fructus Peptaceae，FP）是一种重要的中药，有报道称其具有肝毒性。然而，其机制尚未确定，报道的研究有限。在这项研究中，一个串联的质量标签（TMT）为基础的定量蛋白质组学和代谢组学被用来揭示一个更全面的影响所造成的FP。结果表明，FP水提物可引起大鼠肝损伤。通过定量蛋白质组学分析，共鉴定出575个显著变化的蛋白质，其中352个蛋白质在肝组织中显著上调，223个蛋白质在肝组织中显著下调。检测了琥珀酸、次黄嘌呤、L-肉毒碱、苯丙氨酸、谷胱甘肽、甘氨熊去氧胆酸等14种生物标志物。代谢产物和蛋白质的相关性分析显示，胆汁分泌、谷胱甘肽代谢、嘌呤代谢、甘油磷脂代谢、TCA循环和丙酮酸代谢等代谢途径的异常调节，提示胆汁酸代谢、氧化应激、能量代谢和免疫系统的紊乱。其中Cyp 7a 1、FXR、SHP、BSEP、Sult 2a 1、Nceh 1等胆汁酸代谢蛋白的改变可能在FP水提物的肝毒性中起重要作用。总之，整合蛋白质组学和代谢组学提供了潜在的机制，肝毒性诱导FP.Significance：枸杞子，一种传统的中药，被广泛用于治疗骨质疏松症和白癜风在亚洲。近年来，临床和实验研究发现FP可引起肝损伤。然而，FP引起的损伤机制尚不清楚。本研究采用基于TMT的定量蛋白质组学方法检测了352个肝组织中显著上调的蛋白质和223个肝组织中显著下调的蛋白质。代谢组学分析鉴定出14个重要代谢产物。通过对关键代谢产物和蛋白质的综合分析，筛选出与胆汁酸代谢、氧化应激、能量代谢、免疫系统等相关的代谢途径。这是首次对FP暴露进行蛋白质组学和代谢组学的整合研究，阐明了FP肝毒性的潜在机制，将促进FP在临床上的合理应用。
Fructus Psoraleae (FP), one of the significant traditional Chinese medicines, has been reported to cause hepatotoxicity. However, the mechanism remains undetermined and the reported research is limited. In this study, a tandem mass tag (TMT)-based quantitative proteomics and metabolomics were used to reveal a more comprehensive effect caused by FP. The results showed that aqueous extract of FP can induce liver injury in rats. In total, 575 significantly changed proteins were identified by quantitative proteomics analysis, among which 352 proteins were significantly up-regulated and 223 proteins were significantly down-regulated in liver tissues. And we detected 14 biomarkers such as succinic acid, hypoxanthine, L-carnitine, phenylalanine, glutathione, and glycoursodeoxycholic acid. Correlation analysis of altered metabolites and proteins exhibited the aberrant regulation of metabolic pathways including bile secretion, glutathione metabolism, purine metabolism, glycerophospholipid metabolism, TCA cycle and pyruvate metabolism, which indicated the disorder of bile acid metabolism, oxidative stress, energy metabolism and immune system. Notably, the changed proteins including Cyp7a1, FXR, SHP, BSEP, Sult2a1, Nceh1 in bile acid metabolism may play an essential role in the hepatotoxicity induced by aqueous extract of FP. In conclusion, integrative proteomics and metabolomics provide the potential mechanism of hepatotoxicity induced by FP.Significance: Fructus Psoraleae, a traditional Chinese medicine, is widely used in Asia for the treatment of osteoporosis and vitiligo. Recently, clinical and experimental reports reveal that FP can induce liver injury. However the mechanism of injury induced by FP is still unclear. In this study, we detected 352 significantly upregulated proteins and 223 significantly down-regulated proteins in liver tissues by TMT-based quantitative proteomics. And 14 important metabolites were identified by metabolomics analysis. Through integrative analysis of the key metabolites and proteins, several metabolism pathways were selected, which implicated in bile acid metabolism, oxidative stress, energy metabolism, immune system. This is the first integrative study of proteomics and metabolomics for FP exposure, the finding clarified the potential mechanism of hepatotoxicity caused by FP and will promote rational use of FP in clinical application.