Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, China.
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, China.
FEBS J. 2017 Jan;284(1):114-133. doi: 10.1111/febs.13956. Epub 2016 Nov 29.
Portal hypertension is a frequent pathological symptom occurring especially in hepatic fibrosis and cirrhosis. Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous in vitro study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis-related portal hypertension still requires clarification. In this study, gain- and loss-of-function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl -caused hepatic fibrosis and portal hypertension. Immunofluorescence staining visually showed a decrease in FXR expression in CCl -administrated rat HSC but an increase in that in DHA-treated rat HSC. Serum diagnostics and morphological analyses consistently indicated that DHA exhibited hepatoprotective effects on CCl -induced liver injury. DHA also reduced CCl -caused inflammatory mediator expression and inflammatory cell infiltration. These improvements were further enhanced by INT-747 but weakened by Z-guggulsterone. Noteworthily, DHA, analogous to INT-747, significantly lowered portal vein pressure and suppressed fibrogenesis. Experiments on mice using FXR shRNA lentivirus consolidated the results above. Mechanistically, inhibition of HSC activation and contraction was found as a cellular basis for DHA to relieve portal hypertension. These findings demonstrated that DHA attenuated portal hypertension in fibrotic rodents possibly by targeting HSC contraction via a FXR activation-dependent mechanism. FXR could be a target molecule for reducing portal hypertension during hepatic fibrosis.
门脉高压是一种常见的病理症状，尤其在肝纤维化和肝硬化中发生。目前的范式表明，抑制肝星状细胞（HSC）的激活和收缩预计将是一种有吸引力的治疗策略，因为激活的 HSC 通过分泌细胞外基质和收缩，主要促进肝内静脉压的增加。我们之前的体外研究表明，双氢青蒿素（DHA）通过激活细胞内法尼醇 X 受体（FXR）抑制培养的 HSC 的收缩性。然而，DHA 对纤维化相关的门脉高压的影响仍需要澄清。在这项研究中，建立了 HSC 中 FXR 的获得和缺失功能模型，以研究 DHA 对慢性 CCl 引起的肝纤维化和门脉高压的保护机制。免疫荧光染色直观地显示 CCl 处理的大鼠 HSC 中 FXR 表达减少，但 DHA 处理的大鼠 HSC 中 FXR 表达增加。血清诊断和形态分析一致表明，DHA 对 CCl 引起的肝损伤具有肝保护作用。DHA 还降低了 CCl 引起的炎症介质表达和炎症细胞浸润。这些改善作用被 INT-747 进一步增强，被 Z-金合欢素减弱。值得注意的是，DHA 与 INT-747 类似，显著降低门静脉压力并抑制纤维发生。使用 FXR shRNA 慢病毒的小鼠实验巩固了上述结果。从机制上讲，抑制 HSC 的激活和收缩被发现是 DHA 缓解门脉高压的细胞基础。这些发现表明，DHA 通过 FXR 激活依赖性机制通过靶向 HSC 收缩来减轻纤维化啮齿动物的门脉高压。FXR 可能是减少肝纤维化过程中门脉高压的靶分子。
