GSTA3蛋白对肝纤维化的作用及机制研究

Hepatic fibrosis is a serious problem to human health, the mortality of liver cirrhosis is very high, so preventing liver fibrosis is a key point to prevent liver cirrhosis from occurring and developing. Since oxidative stress and lipid peroxidation play important roles in the pathogenesis of liver fibrosis, it could be a potential therapeutic target. Glutathione S-transferase alpha-3(GSTA3) is a newly discovered antioxidant regulation associated protein with important anti-oxidative activity. Previous study of our group showed that the expression of GSTA3 was significantly decreased in DMN-induced liver fibrosis rats, and GSTA3 levels in hepatic stellate cells (HSC) were decreased after stimulation by TGF-β1 or AngII. However, treatment of the anti-fibrosis new drug--Fluorofenidone(AKF-PD) greatly increased the expression of GSTA3 and remarkably improved liver fibrosis compared to models. Thus, we hypothesized that GSTA3 may play an important protective role in liver fibrosis, and could be a promising target of the anti-fibrosis drug AKF-PD. Based on the above work, the researches we want to conduct in this project are as follow: I. clarifying the effect of GSTA3 in HSC activation and proliferation as well as liver fibrosis; II. illustrating the specific mechanism of the protective role of GSTA3 in liver fibrosis; III. exploring whether GSTA3 is a target of AKF-PD.

肝纤维化严重危害人类健康，肝硬化死亡率高。控制肝纤维化是控制肝硬化发生发展的关键。氧化应激及脂质过氧化是肝纤维化重要发病机制和治疗靶点。Glutathione S-transferase alpha-3（GSTA3）是新近发现的一种抗氧化调节相关蛋白，具有重要的抗氧化活性，本课题组前期研究发现GSTA3在DMN肝纤维化大鼠模型组表达明显降低；TGF-β1、AngII刺激HSC后，GSTA3的表达也明显减少；应用抗肝纤维化新药氟非尼酮治疗后可明显上调GSTA3的表达，同时显著改善肝纤维化程度。由此，我们提出设想：GSTA3可能在肝纤维化过程中对肝脏起重要保护作用，它可能是氟非尼酮治疗肝纤维化的潜在靶点。基于以上研究，本课题组拟对以下问题进行探讨：①明确GSTA3对HSC活化增殖及肝纤维化的影响；②明确GSTA3在肝纤维化中对肝脏起保护作用的具体机制；③明确GSTA3是否为氟非尼酮的作用靶点。

肝纤维化严重危害人类健康，肝硬化死亡率高。控制肝纤维化是控制肝硬化发生发展的关键。氧化应激及脂质过氧化是肝纤维化重要发病机制和治疗靶点。Glutathione S-transferase alpha-3（GSTA3）是新近发现的一种抗氧化调节相关蛋白，具有重要的抗氧化活性，本课题旨在探讨GSTA3在肝纤维化中的作用以及GSTA3是否为氟非尼酮治疗肝纤维化的作用靶点。本课题组通过研究发现：在整体动物实验中，在DMN肝纤维化大鼠模型中，与正常组相比，DMN模型组肝星状细胞明显活化，GSTA3的表达明显降低。进一步通过体外细胞实验观察，结果显示：GSTA3通过参与氧化应激过程，清除脂质过氧化产物，抑制Wnt/β-catenin信号通路，从而抑制肝星状细胞的活化而发挥抗肝纤维化的作用。同时，我们也初步证实，GSTA3是抗肝纤维化新药氟非尼酮的作用靶点。总结：本研究首次发现并证实GSTA3参与了肝纤维化，并在其发生发展中发挥了保护肝脏的作用，这为进一步研究肝纤维化的发病机制及GSTA3在肝纤维化中的作用提供了重要依据，具有重要的科学及临床意义。并且，在本项目的基础上，本课题组自主研发的抗纤维化新药氟非尼酮已被国家食品药品监督管理局批准进入Ⅰ期临床试验，极大的推动了抗肝纤维化治疗药物的发展。

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