PDF(Pubmed)
Abstract：
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.
摘要：
雷公藤甲素(TP),以治疗各种类风湿疾病的有效性而闻名，也与显著的肝毒性风险相关。本研究探索了Catalpol(CAT)，一种具有抗氧化和抗炎作用的环烯醚萜苷，作为对TP诱导的肝损伤的潜在防御。使用TP与不同浓度的CAT组合建立肝损伤的体内和体外模型。进行代谢组学分析以评估小鼠肝脏中的能量代谢。此外,海马XF分析仪用于测量糖酵解速率，线粒体呼吸功能，和AML12细胞中的实时ATP生成速率。该研究还检查了与糖原分解和糖异生相关的蛋白质的表达。使用体外SIRT1敲除/过表达和体内肝脏特异性SIRT1敲除模型，我们证实SIRT1是CAT的一种作用机制。我们的发现表明，CAT可以通过激活SIRT1减轻TP诱导的肝损伤，从而抑制缺氧诱导因子-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。这种作用改善了线粒体功能障碍，并减少了TP引起的葡萄糖代谢紊乱和氧化应激。一起来看,这些见解揭示了迄今为止CAT改善TP诱导的肝损伤的未记录机制，将其定位为管理TP诱导的肝毒性的潜在治疗剂。
