栀子苷通过调节 SIRT1/FXR 信号通路缓解胆酸相关 NLRP3 炎性小体激活在胆管结扎诱导的肝纤维化中的作用。
Geniposide alleviated bile acid-associated NLRP3 inflammasome activation by regulating SIRT1/FXR signaling in bile duct ligation-induced liver fibrosis.
机构信息
Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, PR China.
Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, PR China; Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan.
出版信息
Phytomedicine. 2023 Sep;118:154971. doi: 10.1016/j.phymed.2023.154971. Epub 2023 Jul 18.
BACKGROUND
Geniposide (GE), the active compound derived from Gardeniae Fructus, possesses valuable bioactivity for liver diseases, but GE effects on bile duct ligation (BDL)-induced cholestasis remain unclear. This study aimed to elucidate the influence of GE on BDL-induced liver fibrosis and to investigate the underlying mechanisms.
METHODS
GE (25 or 50 mg/kg) were intragastrical administered to C57BL/6 J mice for two weeks to characterize the hepatoprotective effect of GE on BDL-induced liver fibrosis. NLRP3 inflammasome activation was detected in vivo, and BMDMs were isolated to explore whether GE directly inhibited NLRP3 inflammasome activation. Serum bile acid (BA) profiles were assessed utilizing UPLC-MS/MS, and the involvement of SIRT1/FXR pathways was identified to elucidate the role of SIRT1/FXR in the hepaprotective effect of GE. The veritable impact of SIRT1/FXR signaling was further confirmed by administering the SIRT1 inhibitor EX527 (10 mg/kg) to BDL mice treated with GE.
RESULTS
GE treatment protected mice from BDL-induced liver fibrosis, with NLRP3 inflammasome inhibition. However, development in vitro experiments revealed that GE could not directly inhibit NLRP3 activation under ATP, monosodium urate, and nigericin stimulation. Further mechanistic data showed that GE activated SIRT1, which subsequently deacetylated FXR and restored CDCA, TUDCA, and TCDCA levels, thereby contributing to the observed hepaprotective effect of GE. Notably, EX527 treatment diminished the hepaprotective effect of GE on BDL-induced liver fibrosis.
CONCLUSION
This study first proved the hepaprotective effect of GE on liver fibrosis in BDL mice, which was closely associated with the restoration of BA homeostasis and NLRP3 inflammasome inhibition. The activation of SIRT1 and the subsequent FXR deacetylation restored the BA profiles, especially CDCA, TUDCA, and TCDCA contents, which was the main contributor to NLRP3 inhibition and the hepaprotective effect of GE. Overall, our work provides novel insights that GE as well as Gardeniae Fructus might be the potential attractive candidate for ameliorating BDL-induced liver fibrosis.
背景
栀子苷（GE）是从栀子果实中提取的活性化合物，对肝脏疾病具有重要的生物活性，但 GE 对胆管结扎（BDL）诱导的胆汁淤积的影响尚不清楚。本研究旨在阐明 GE 对 BDL 诱导的肝纤维化的影响，并探讨其潜在机制。
方法
用 25 或 50mg/kg 的 GE 灌胃 C57BL/6J 小鼠两周，以研究 GE 对 BDL 诱导的肝纤维化的保护作用。在体内检测 NLRP3 炎性体的激活，分离 BMDMs 以探讨 GE 是否直接抑制 NLRP3 炎性体的激活。利用 UPLC-MS/MS 评估血清胆汁酸（BA）谱，并确定 SIRT1/FXR 途径的参与，以阐明 SIRT1/FXR 在 GE 的肝保护作用中的作用。通过给予 SIRT1 抑制剂 EX527（10mg/kg）进一步证实 SIRT1/FXR 信号的真正影响，给予 GE 治疗的 BDL 小鼠。
结果
GE 治疗可保护小鼠免受 BDL 诱导的肝纤维化，抑制 NLRP3 炎性体的激活。然而，体外实验结果表明，在 ATP、单钠尿酸盐和 Nigericin 刺激下，GE 不能直接抑制 NLRP3 的激活。进一步的机制数据表明，GE 激活 SIRT1，随后去乙酰化 FXR 并恢复 CDCA、TUDCA 和 TCDCA 水平，从而有助于观察到的 GE 的肝保护作用。值得注意的是，EX527 处理减弱了 GE 对 BDL 诱导的肝纤维化的肝保护作用。
结论
本研究首次证明了 GE 对 BDL 小鼠肝纤维化的肝保护作用，这与 BA 动态平衡的恢复和 NLRP3 炎性体的抑制密切相关。SIRT1 的激活和随后的 FXR 去乙酰化恢复了 BA 谱，特别是 CDCA、TUDCA 和 TCDCA 的含量，这是 NLRP3 抑制和 GE 肝保护作用的主要原因。总的来说，我们的工作提供了新的见解，即 GE 和栀子可能是改善 BDL 诱导的肝纤维化的有吸引力的候选药物。
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