Li Xi, Jin Qianwen, Yao Qunyan, Xu Beili, Li Zheng, Tu Chuantao
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai Institute of Liver Diseases, Shanghai, China; Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai Institute of Liver Diseases, Shanghai, China.
Toxicol Lett. 2016 Nov 2;261:1-12. doi: 10.1016/j.toxlet.2016.09.002. Epub 2016 Sep 4.
This study aimed to investigate the effects of quercetin on liver fibrogenesis in mice and to elucidate the underlying molecular mechanisms. Mice were administered with carbon tetrachloride (CCl) for eight weeks to induce liver fibrosis and concomitantly orally treated with quercetin (50mgkgday). Here, we demonstrated that quercetin dramatically ameliorated liver injury, inflammation, and hepatic fibrogenesis induced by CCl. Quercetin also inhibited the activation of hepatic stellate cells (HSC) in vivo and in vitro, as evaluated by α-smooth muscle actin (α-SMA) expression, which is a specific marker of HSC activation. Moreover, reduced fibrosis was associated with decreased high-mobility group box 1 (HMGB1), toll like receptor (TLR) 2 and TLR4 genes, and protein expression. Quercetin also inhibited the cytoplasmic translocation of HMGB1 in hepatocytes of fibrotic livers. Further investigation demonstrated that quercetin treatment significantly attenuated CCl-induced nuclear translocation of the nuclear factor-κB (NF-κB) p65 and inhibited degradation of IκBα (an inhibitor of NF-κB) expression in the liver compared with vehicle-treated fibrotic mice. Considered together, our data indicate that quercetin has hepatoprotective and anti-fibrotic effects in animal models of liver fibrosis, the mechanism of which may be involved in modulating the HMGB1-TLR2/4-NF-κB signaling pathways.
本研究旨在探讨槲皮素对小鼠肝纤维化形成的影响，并阐明其潜在的分子机制。给小鼠连续八周注射四氯化碳（CCl）以诱导肝纤维化，同时口服槲皮素（50mg/kg/天）。在此，我们证明槲皮素能显著改善由CCl诱导的肝损伤、炎症和肝纤维化形成。通过α平滑肌肌动蛋白（α-SMA）表达评估（α-SMA是肝星状细胞（HSC）激活的特异性标志物），槲皮素在体内和体外还能抑制HSC的激活。此外，纤维化减轻与高迁移率族蛋白B1（HMGB1）、Toll样受体（TLR）2和TLR4基因及蛋白表达降低有关。槲皮素还抑制纤维化肝脏中肝细胞内HMGB1的细胞质转位。进一步研究表明，与溶剂处理的纤维化小鼠相比，槲皮素治疗显著减弱了CCl诱导的核因子κB（NF-κB）p65的核转位，并抑制了肝脏中IκBα（NF-κB的抑制剂）表达的降解。综合来看，我们的数据表明槲皮素在肝纤维化动物模型中具有肝保护和抗纤维化作用，其机制可能涉及调节HMGB1-TLR2/4-NF-κB信号通路。
