Asiatic acid inhibits liver fibrosis by blocking TGF-beta/Smad signaling in vivo and in vitro.
Asiatic acid inhibits liver fibrosis by blocking TGF-beta/Smad signaling in vivo and in vitro.
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亚洲酸通过在体内和体外阻断TGF-β/SMAD信号传导来抑制肝纤维化。
DOI：
10.1371/journal.pone.0031350
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lan HY
中科院分区：
文献类型：
--
作者：
Tang LX;He RH;Yang G;Tan JJ;Zhou L;Meng XM;Huang XR;Lan HY
肝纤维化是肝衰竭的主要原因，但治疗仍然无效。在本研究中，我们研究了积雪草酸（AA）在四氯化碳（CCl 4）诱导的大鼠肝纤维化模型和体外TGF-β 1刺激的大鼠肝星状细胞系（HSC-T6）中的抗肝纤维化活性和机制。AA治疗以剂量依赖性方式显著减轻CCl 4诱导的肝纤维化和功能损害，包括通过抑制从头α平滑肌肌动蛋白（α-SMA）和胶原基质表达以及ALT和AST升高（均p<0.01）确定的HSC活化阻断。AA对肝纤维化的保护作用与肝Smad 7（TGF-β信号传导抑制剂）的上调有关，从而阻断TGF-β 1和CTGF的上调以及TGF-β/Smad信号传导的激活。进一步在体外HSC-T6中检测AA的抗纤维化活性及其机制。添加AA显著诱导HSC-T6细胞的Smad 7表达，从而以剂量依赖性方式抑制TGF-β 1诱导的Smad 2/3活化、肌成纤维细胞转化和胶原基质表达。相反，HSC-T6细胞中Smad 7的敲低阻止了AA诱导的HSC-T6细胞活化抑制和对TGF-β 1的纤维化反应，揭示了Smad 7在体内和体外肝纤维化过程中AA诱导的抗纤维化活性中的重要作用。结论：AA可能是一种新的治疗肝纤维化的药物。Smad 7依赖性抑制TGF-β/Smad介导的肝纤维化可能是AA保护肝脏免受损伤的重要机制。
Liver fibrosis is a major cause of liver failure, but treatment remains ineffective. In the present study, we investigated the mechanisms and anti-hepatofibrotic activities of asiatic acid (AA) in a rat model of liver fibrosis induced by carbon tetrachloride (CCl4) and in vitro in TGF-beta1-stimulated rat hepatic stellate cell line (HSC-T6). Treatment with AA significantly attenuated CCl4-induced liver fibrosis and functional impairment in a dosage-dependent manner, including blockade of the activation of HSC as determined by inhibiting de novo alpha smooth muscle actin (a-SMA) and collagen matrix expression, and an increase in ALT and AST (all p<0.01). The hepatoprotective effects of AA on fibrosis were associated with upregulation of hepatic Smad7, an inhibitor of TGF-beta signaling, thereby blocking upregulation of TGF-beta1 and CTGF and the activation of TGF-beta/Smad signaling. The anti-fibrosis activity and mechanisms of AA were further detected in vitro in HSC-T6. Addition of AA significantly induced Smad7 expression by HSC-T6 cells, thereby inhibiting TGF-beta1-induced Smad2/3 activation, myofibroblast transformation, and collagen matrix expression in a dosage-dependent manner. In contrast, knockdown of Smad7 in HSC-T6 cells prevented AA-induced inhibition of HSC-T6 cell activation and fibrosis in response to TGF-beta1, revealing an essential role for Smad7 in AA-induced anti-fibrotic activities during liver fibrosis in vivo and in vitro. In conclusion, AA may be a novel therapeutic agent for liver fibrosis. Induction of Smad7-dependent inhibition of TGF-beta/Smad-mediated fibrogenesis may be a central mechanism by which AA protects liver from injury.
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