SIRT7介导H3K18组蛋白特异位点去乙酰化在砷致肝纤维化中的作用及机制研究

The liver injury and its malignant prognosis induced by arsenic exposure is one of the health risks of endemic arsenism. Liver fibrosis is a key stage for liver injury progressing to cirrhosis and eventually to liver failuer or malignancy. To clarify the mechanism and reveal the potential pathway of arsenic-induced liver fibrosis play an important role in the prevention of the risk of liver injury malignant prognosis caused by arsenic. Howerver, the mechanism underlying the arsenic-induced liver fibrosis remained unclear. Epigenetic modifications, especially histone acetylation is considered to be a critical mechanism for liver fibrogenesis and its reversible process. Notably, the evidence indicates that SIRT7 specifically deacetylates H3K18ac might be an novel pathway to ragulate the liver fibrogenesis. Moreover, the assosiation between H3K18ac and arsenic toxity or arsenicosis provided evidence that alteration H3K18ac might be involved in regulation of arsenicosis. On the basis of these evidences, rat model of arsenic-induced liver fibrosis would be established to explore whether SIRT7/H3K18ac play a role in regulation of arsenic-induced liver fibrosis. In addition, this study attempt to reveal the potential pathway regulated by SIRT7/H3K18ac to explian the machainem of arsenic-induced liver fibrosis, which hopefully contribute to the identification of novel targets to monitor and prevent the arsenic-induced liver fibrogenesis and malignant resolution.

砷诱导的肝损伤及其恶性转归是目前地方性砷中毒病区健康隐患之一。肝纤维化是砷中毒肝损伤向肝硬化、肝癌等发展的重要阶段，探讨砷致肝纤维化毒作用机制及关键毒性通路对砷中毒肝损伤恶性转归防控有重要意义。目前砷致肝纤维化机制尚不明确。近期研究显示表观遗传，特别是组蛋白乙酰化是调控肝纤维化形成及逆转的关键机制，组蛋白去乙酰化酶SIRT7介导的H3K18特异位点去乙酰化是肝纤维化表观遗传调控关键靶点。有研究表明H3K18ac与砷早期毒效应及砷中毒密切相关，提示其可能是调控砷中毒的特异表观遗传修饰，但其在砷中毒中的作用及机制迄今尚不清楚。本研究拟以SIRT7/H3K18ac调控轴为切入点，通过构建砷致肝纤维化大鼠模型，探讨SIRT7/H3K18ac在砷致肝纤维化中的作用；并结合体外细胞实验，揭示SIRT7/H3K18ac介导砷致肝纤维化表观遗传机制，为砷中毒肝损伤恶性转归提供新的监测靶点及防控手段。

对停止高砷暴露后砷中毒人群肝损伤的渐进性不可逆发展进行早期监测和干预，是目前地砷病防控亟待解决的问题。肝纤维化是砷中毒肝损伤向肝硬化、肝癌等发展的重要阶段，探讨砷致肝纤维化毒作用机制、揭示关键毒性通路对砷中毒肝损伤恶性转归的防控有重要意义。因此，本研究以SIRT7/H3K18ac调控轴为切入点，结合砷致大鼠肝纤维化时效、量效模型及体外肝星状细胞活化模型，系统地阐明了SIRT7/H3K18ac调控轴在砷致肝纤维化发生及发展中的作用，揭示了以SIRT7/H3K18ac调控轴为核心的砷致肝纤维化表观遗传调控网络，并探讨了SIRT7干预对砷致肝纤维化的抑制作用及机制。主要结果如下：1. 砷诱导的SIRT7/H3K18ac调控轴改变可启动砷致慢性肝损伤向肝纤维化转变、并调控砷致肝纤维化的进行性加重，提示SIRT7/H3K18ac调控轴对砷中的肝损病程进展有潜在预警作用。2. 砷暴露介导的SIRT7/H3K18ac调控轴改变通过诱导肝星状细胞活化调节砷致肝纤维化发生发展，具体调控网络如下：①诱导SIRT7表达增加，减少H3K18总体乙酰化水平，直接调节肝星状细胞活化及肝纤维化的发生发展；②诱导SIRT7表达增加，促进肝星状细胞活化相关基因VEGFC、HIF-1α表达，参与肝星状细胞活化及肝纤维化的发生发展；③诱导肝星状细胞活化相关基因VEGFC、HIF-1α启动子区H3K18ac富集增加，促进基因表达，调节肝星状细胞活化及肝纤维化的发生发展。3. 抑制砷诱导的SIRT7表达增加可通过恢复H3K18总体乙酰化水平、阻止肝星状细胞活化相关基因VEGFC、HIF-1α异常高表达，拮抗砷诱导的肝星状细胞活化及肝纤维化。 本研究为砷中毒肝损伤敏感病程阶段的早期识别提供了潜在的生物学标志，为砷中毒肝损伤风险预测及早期干预提供了新靶点。