Xu Jie, Xue Qiongwen, Xiong Aizhen, Chen Yilin, Wang Xunjiang, Yan Xing, Ruan Deqing, Zhang Yumeng, Wang Zhengtao, Ding Lili, Yang Li
Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Department of Pharmacy, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China.
Chin Med. 2025 Mar 12;20(1):34. doi: 10.1186/s13020-025-01077-2.
Pyrrolizidine alkaloids (PAs), recognized globally for their hepatotoxic properties, significantly contribute to liver damage through an imbalance in bile acid homeostasis. Addressing this imbalance is crucial for therapeutic interventions in PA-related liver injuries. Chlorogenic acid (Cga), a phenolic compound derived from medicinal plants, has demonstrated hepato-protective effects across a spectrum of liver disorders. The specific influence and underlying mechanisms by which Cga mitigates PA-induced liver damage have not been clearly defined.
To explore the protective effects of Cga against acute PA toxicity, a murine model was established. The influence of Cga on bile acid metabolism was confirmed through a variety of molecular biology techniques. These included RNA sequencing, western blotting, and immunoprecipitation, along with quantitative analyses of bile acid concentrations.
Our findings indicate that Cga enhances sirtuin 1 (SIRT1) activation and increases farnesoid X receptor (FXR) signaling, which are crucial for maintaining bile acid balance in PA-induced hepatic injury. When mice subjected to PA-induced hepatic injury were treated with SIRT1 inhibitors alongside Cga, the hepatoprotective effects of Cga were significantly reduced. In Fxr-KO mice, the ability of Cga to mitigate liver damage induced by PAs was substantially reduced, which underscores the role of the SIRT1/FXR signaling axis in mediating the protective effects of Cga.
Our research suggests that Cga can serve as an effective treatment for PA-mediated hepatotoxicity. It appears that influencing the SIRT1/FXR signaling pathway might provide an innovative pharmacological approach to address liver damage caused by PAs.
吡咯里西啶生物碱（PAs）因其肝毒性在全球范围内受到关注，通过胆汁酸稳态失衡对肝脏造成显著损害。解决这种失衡对于PA相关肝损伤的治疗干预至关重要。绿原酸（Cga）是一种从药用植物中提取的酚类化合物，已在一系列肝脏疾病中显示出肝脏保护作用。Cga减轻PA诱导的肝损伤的具体影响和潜在机制尚未明确。
为了探究Cga对急性PA毒性的保护作用，建立了小鼠模型。通过多种分子生物学技术证实了Cga对胆汁酸代谢的影响。这些技术包括RNA测序、蛋白质免疫印迹和免疫沉淀，以及胆汁酸浓度的定量分析。
我们的研究结果表明，Cga增强了沉默调节蛋白1（SIRT1）的激活并增加了法尼酯X受体（FXR）信号传导，这对于维持PA诱导的肝损伤中的胆汁酸平衡至关重要。当用SIRT1抑制剂与Cga联合处理PA诱导的肝损伤小鼠时，Cga的肝脏保护作用显著降低。在FXR基因敲除小鼠中，Cga减轻PA诱导的肝损伤的能力大幅降低，这突出了SIRT1/FXR信号轴在介导Cga保护作用中的作用。
我们的研究表明，Cga可作为PA介导的肝毒性的有效治疗方法。影响SIRT1/FXR信号通路似乎可能为解决PA引起的肝损伤提供一种创新的药理学方法。
