多组学分析揭示木脂素对乙酰氨基酚诱导的肝毒性的保护作用。
Multiomics Profiling Reveals Protective Function of Lignans against Acetaminophen-Induced Hepatotoxicity.
机构信息
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People's Hospital), Nanjing, P.R. China (Q.D.).
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People's Hospital), Nanjing, P.R. China (Q.D.)
出版信息
Drug Metab Dispos. 2020 Oct;48(10):1092-1103. doi: 10.1124/dmd.120.000083. Epub 2020 Jul 27.
The action principles of traditional Chinese medicines (TCMs) feature multiactive components, multitarget sites, and weak combination with action targets. In the present study, we performed an integrated analysis of metabonomics, proteomics, and lipidomics to establish a scientific research system on the underlying mechanism of TCMs, and lignan extract (SLE) was selected as a model TCM. In metabonomics, several metabolic pathways were found to mediate the liver injury induced by acetaminophen (APAP), and SLE could regulate the disorder of lipid metabolism. The proteomic study further proved that the hepatoprotective effect of SLE was closely related to the regulation of lipid metabolism. Indeed, the results of lipidomics demonstrated that SLE dosing has an obvious callback effect on APAP-induced lipidic profile shift. The contents of 25 diglycerides (DAGs) and 21 triglycerides (TAGs) were enhanced significantly by APAP-induced liver injury, which could further induce liver injury and inflammatory response by upregulating protein kinase C (PKC, PKC, PKC, and PKC). The upregulated lipids and PKCs could be reversed to the normal level by SLE dosing. More importantly, phosphatidic acid phosphatase, fatty acid transport protein 5, and diacylglycerol acyltransferase 2 were proved to be positively associated with the regulation of DAGs and TAGs. SIGNIFICANCE STATEMENT: Integrated multiomics was first used to reveal the mechanism of APAP-induced acute liver failure (ALF) and the hepatoprotective role of SLE. The results showed that the ALF caused by APAP was closely related to lipid regulation and that SLE dosing could exert a hepatoprotective role by reducing intrahepatic diglyceride and triglyceride levels. Our research can not only promote the application of multicomponent technology in the study of the mechanism of traditional Chinese medicines but also provide an effective approach for the prevention and treatment of ALF.
中药的作用机制具有多活性成分、多靶点和与作用靶点弱结合的特点。本研究采用代谢组学、蛋白质组学和脂质组学的综合分析方法，建立了中药作用机制的科学研究体系，选择木脂素提取物（SLE）作为中药模型。在代谢组学中，发现了几种代谢途径来介导对乙酰氨基酚（APAP）引起的肝损伤，SLE 可以调节脂代谢紊乱。蛋白质组学研究进一步证明，SLE 的保肝作用与脂代谢调节密切相关。事实上，脂质组学的结果表明，SLE 给药对 APAP 诱导的脂质谱变化具有明显的回调作用。25 种二酰基甘油（DAG）和 21 种三酰基甘油（TAG）的含量因 APAP 引起的肝损伤而显著增加，这可通过上调蛋白激酶 C（PKC、PKC、PKC 和 PKC）进一步引起肝损伤和炎症反应。SLE 给药可使上调的脂质和 PKCs 恢复到正常水平。更重要的是，证实了磷酸酶、脂肪酸转运蛋白 5 和二酰基甘油酰基转移酶 2 与 DAG 和 TAG 的调节呈正相关。意义陈述：首次采用集成多组学方法揭示 APAP 诱导的急性肝衰竭（ALF）的机制和 SLE 的保肝作用。结果表明，APAP 引起的 ALF 与脂质调节密切相关，SLE 给药可通过降低肝内二酰基甘油和三酰基甘油水平发挥保肝作用。我们的研究不仅可以促进中药多成分技术在作用机制研究中的应用，而且为 ALF 的防治提供了一种有效的方法。
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