代谢组学揭示了 PPARα 在雷公藤致肝损伤中的作用。
Metabolomics reveals the role of PPARα in Tripterygium Wilfordii-induced liver injury.
机构信息
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China.
出版信息
J Ethnopharmacol. 2022 May 10;289:115090. doi: 10.1016/j.jep.2022.115090. Epub 2022 Feb 7.
ETHNOPHARMACOLOGICAL RELEVANCE
Tripterygium glycosides tablets (TGT) and Tripterygium wilfordii tablets (TWT) have been used to treat autoimmune diseases clinically, however, the side effects of TWT are higher than TGT, especially for hepatotoxicity.
THE AIM OF THE STUDY
This study aims to determine the mechanism of TWT-induced liver injury.
MATERIALS AND METHODS
We performed metabolomic analysis of samples from mice with liver injury induced by TGT and TWT. Ppara-null mice were used to determine the role of PPARα in TWT-induced liver injury.
RESULTS
The results indicated that TWT induced the accumulation of medium- and long-chain carnitines metabolism, which was associated with the disruption of PPARα-IL6-STAT3 axis. PPARα agonists fenofibrate could reverse the liver injury from TWT and TP/Cel, and its protective role could be attenuated in Ppara-null mice. The toxicity difference of TWT and TGT was due to the different ratio of triptolide (TP) and celastrol (Cel) in the tablet in which TP/Cel was lower in TWT than TGT. The hepatotoxicity induced by TP and Cel also inhibited PPARα and upregulated IL6-STAT3 axis, which could be alleviated following by PPARα activation.
CONCLUSIONS
These results indicated that PPARα plays an important role in the hepatotoxicity of Tripterygium wilfordii, and PPARα activation may offer a promising approach to prevent hepatotoxicity induced by the preparations of Tripterygium wilfordii.
民族药理学相关性
雷公藤多苷片（TGT）和雷公藤多苷片（TWT）已被用于临床治疗自身免疫性疾病，但 TWT 的副作用高于 TGT，尤其是肝毒性。
研究目的
本研究旨在确定 TWT 诱导肝损伤的机制。
材料和方法
我们对 TGT 和 TWT 诱导的肝损伤小鼠样本进行了代谢组学分析。使用 Ppara 基因敲除小鼠来确定 PPARα 在 TWT 诱导的肝损伤中的作用。
结果
结果表明，TWT 诱导中链和长链肉碱代谢物的积累，与 PPARα-IL6-STAT3 轴的破坏有关。PPARα 激动剂非诺贝特可以逆转 TWT 和 TP/Cel 引起的肝损伤，并且其在 Ppara 基因敲除小鼠中的保护作用会减弱。TWT 和 TGT 的毒性差异归因于片剂中雷公藤内酯（TP）和雷公藤红素（Cel）的比例不同，TWT 中的 TP/Cel 低于 TGT。TP 和 Cel 引起的肝毒性也抑制了 PPARα，并上调了 IL6-STAT3 轴，而 PPARα 的激活可以减轻这种情况。
结论
这些结果表明，PPARα 在雷公藤的肝毒性中起着重要作用，激活 PPARα 可能为预防雷公藤制剂引起的肝毒性提供一种有前途的方法。
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