Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.
Pharmacy Department of Affiliated Zhongshan Hospital of Dalian University, Dalian, China.
Int Immunopharmacol. 2019 Oct;75:105833. doi: 10.1016/j.intimp.2019.105833. Epub 2019 Aug 23.
Hepatic fibrosis is a reversible would-healing response following chronic liver injury of different aetiologies and represents a major worldwide health problem. Up to date, there is no satisfactory drugs treated for liver fibrosis. The present study was to investigate hepatoprotection of yangonin against liver fibrosis induced by thioacetamide (TAA) in mice and further to clarify the involvement of farnesoid X receptor (FXR) in vivo and in vitro. Yangonin treatment remarkably ameliorated TAA-induced liver injury by reducing relative liver weight, as well as serum ALT and AST activities. Moreover, yangonin alleviated TAA-induced accumulation of bile acids through increasing the expression of bile acid efflux transporters such as Bsep and Mrp2, and reducing hepatic uptake transporter Ntcp expression, all of these are FXR-target genes. The liver sections stained by H&E indicated that the histopathological change induced by TAA was improved by yangonin. Masson and Sirius red staining indicated the obvious anti-fibrotic effect of yangonin. The mechanism of anti-fibrotic effect of yangonin was that yangonin reduced collagen content by regulating the genes involved in hepatic fibrosis including COL1-α1 and TIMP-1. Besides, yangonin inhibited hepatic stellate cell activation by reducing TGF-β1 and α-SMA expression. In addition, yangonin protected against TAA-induced hepatic inflammation via its inhibition of NF-κB and TNF-α. These hepatoprotective effects of yangonin were abrogated by guggulsterone which is a FXR antagonist. In vitro experiment further demonstrated dose-dependent activation of FXR by yangonin using dual-luciferase reporter assay. In summary, yangonin produces hepatoprotection against TAA-induced liver fibrosis via FXR activation.
肝纤维化是一种对不同病因的慢性肝损伤的可逆转的组织修复反应，是一个全球性的主要健康问题。迄今为止，尚无满意的药物可用于治疗肝纤维化。本研究旨在探讨羊蹄甲素（yangonin）对硫代乙酰胺（TAA）诱导的小鼠肝纤维化的保护作用，并进一步阐明其在体内和体外对法尼醇 X 受体（FXR）的作用。羊蹄甲素治疗可显著改善 TAA 诱导的肝损伤，降低相对肝重、血清 ALT 和 AST 活性。此外，羊蹄甲素通过增加胆汁酸外排转运体如 Bsep 和 Mrp2 的表达，并降低肝摄取转运体 Ntcp 的表达，减轻 TAA 诱导的胆汁酸蓄积，这些都是 FXR 靶基因。H&E 染色的肝切片表明，羊蹄甲素改善了 TAA 诱导的组织学变化。Masson 和 Sirius red 染色表明，羊蹄甲素具有明显的抗纤维化作用。羊蹄甲素抗纤维化作用的机制是通过调节肝纤维化相关基因，包括 COL1-α1 和 TIMP-1，减少胶原含量。此外，羊蹄甲素通过降低 TGF-β1 和 α-SMA 的表达抑制肝星状细胞的激活。此外，羊蹄甲素通过抑制 NF-κB 和 TNF-α 来防止 TAA 诱导的肝炎症。这些羊蹄甲素的肝保护作用被 FXR 拮抗剂金合欢素所阻断。体外实验进一步通过双荧光素酶报告基因检测证实了羊蹄甲素对 FXR 的剂量依赖性激活。综上所述，羊蹄甲素通过激活 FXR 对 TAA 诱导的肝纤维化产生肝保护作用。
