梓醇通过调节SIRT1/HIF-1α途径减轻三苯氧胺诱导的肝损伤中的肝糖代谢紊乱和氧化应激。

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
International Journal of Biological Sciences Pub Date : 2024-08-01 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.97362
Weijue Nie, Hong Zhu, Xin Sun, Jie Zhou, Heng Xu, Zhichao Yu, Minghao Lu, Baoping Jiang, Lingling Zhou, Xueping Zhou
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引用次数: 0

摘要

雷公藤内酯(Triptolide,TP)因其在治疗各种类风湿疾病方面的功效而闻名,但它也有很大的肝毒性风险。本研究探讨了具有抗氧化和抗炎作用的鸢尾甙--梓醇(CAT),将其作为防止 TP 引起的肝损伤的潜在疗法。通过将 TP 与不同浓度的 CAT 结合使用,建立了肝损伤的体内和体外模型。代谢组学分析评估了小鼠肝脏的能量代谢。此外,还采用海马 XF 分析仪测量 AML12 细胞的糖酵解率、线粒体呼吸功能和实时 ATP 生成率。研究还检测了与糖原分解和葡萄糖生成有关的蛋白质的表达。利用体外 SIRT1 基因敲除/外显和体内肝脏特异性 SIRT1 基因敲除模型,我们证实了 SIRT1 是 CAT 的作用机制。我们的研究结果表明,CAT 可通过激活 SIRT1 缓解 TP 诱导的肝损伤,SIRT1 可抑制缺氧诱导因子-1α(HIF-1α)的赖氨酸乙酰化,从而恢复糖酵解和氧化磷酸化之间的平衡。这一作用改善了线粒体功能障碍,减少了 TP 引起的葡萄糖代谢紊乱和氧化应激。综上所述,这些见解揭示了一种迄今为止尚未记录的机制,即 CAT 可改善 TP 引起的肝损伤,从而使其成为控制 TP 引起的肝毒性的一种潜在治疗药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Catalpol attenuates hepatic glucose metabolism disorder and oxidative stress in triptolide-induced liver injury by regulating the SIRT1/HIF-1α pathway.

Triptolide (TP), known for its effectiveness in treating various rheumatoid diseases, is also associated with significant hepatotoxicity risks. This study explored Catalpol (CAT), an iridoid glycoside with antioxidative and anti-inflammatory effects, as a potential defense against TP-induced liver damage. In vivo and in vitro models of liver injury were established using TP in combination with different concentrations of CAT. Metabolomics analyses were conducted to assess energy metabolism in mouse livers. Additionally, a Seahorse XF Analyzer was employed to measure glycolysis rate, mitochondrial respiratory functionality, and real-time ATP generation rate in AML12 cells. The study also examined the expression of proteins related to glycogenolysis and gluconeogenesis. Using both in vitro SIRT1 knockout/overexpression and in vivo liver-specific SIRT1 knockout models, we confirmed SIRT1 as a mechanism of action for CAT. Our findings revealed that CAT could alleviate TP-induced liver injury by activating SIRT1, which inhibited lysine acetylation of hypoxia-inducible factor-1α (HIF-1α), thereby restoring the balance between glycolysis and oxidative phosphorylation. This action improved mitochondrial dysfunction and reduced glucose metabolism disorder and oxidative stress caused by TP. Taken together, these insights unveil a hitherto undocumented mechanism by which CAT ameliorates TP-induced liver injury, positioning it as a potential therapeutic agent for managing TP-induced hepatotoxicity.

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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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