NPAS2调节肝细胞EMT促进肝纤维化进展的机制研究

As a precancerous lesion of hepatocellular carcinoma, hepatic fibrosis seriously affect patients’ quality and safety of life. Numbers of studies have shown that excessive production of extracellular matrix by fibroblast-like cells which transformed from various types of liver its is the main mechanism of hepatic fibrosis. Recent studies show that fibroblasts transformed from hepatocytes play an important role in hepatic fibrosis. However, the regulatory mechanism of hepatocytes EMT process is unclear.As a Transcriptional gene, NPAS2 Involved in the regulation including the occurrence of hepatocellular carcinoma. The latest research shows that NPAS2 is closely related to the regulation of cell phenotype in hepatic tissue.Our results show that NPAS2 expression was upregulated in hepatocytes of hepatic fibrosis tissue. This result suggests that it may be associated with the progression of hepatic fibrosis.Further bioinformatics analysis demonstrated itshas the potential to conjunction with the transcriptional initiation region of TGF-β, Which is the most important regulation genes of EMT. Our study also shows that overexpression of NPAS2 cloud promote the expression of fibrin in hepatocytes and promote hepatocytes transformed to fibroblast-like cells. In short，could NPAS2 promote fibrosis via adjust hepatocyte EMT by regulating TGF-β transcription need further study.

肝纤维化作为肝癌的前期病变，其严重影响患者的生活质量及生命安全。大量的实验研究表明肝损伤后肝内多种细胞向成纤维样细胞转化，并由其过度产生细胞外基质是肝纤维化的主要机制。近年来的究显示，肝细胞作为肝脏最大的细胞群体，其通过EMT转化而来的成纤维细胞在肝纤维化过程具有重要作用。但是肝细胞EMT过程的调控机制尚不明确。NPAS2作为转录启动基因参与调控包括肝癌等疾病的发生，最新的研究显示其在肝脏组织中与细胞表型调控密切相关。我们前期的实验研究结果显示，肝纤维化组织中肝细胞NPAS2表达上调，说明其可能与肝纤维化进展相关。进一步的生物信息学分析显示其具有与调节EMT的主要基因TGF-β转录起始区结合的潜能。体外研究显示过表达肝细胞中的NPAS2可以促进肝细胞纤维蛋白的表达及成纤维样细胞特性的出现。NPAS2是否通过调控TFG-β转录而促进肝细胞EMT进而促进肝纤维化及其具体机制有待进一步研究。

肝纤维化严重影响患者的生活质量及生命安全。研究表明肝损伤后肝内成纤维样细胞过度产生细胞外基质是肝纤维化的主要机制。NPAS2作为转录启动基因参与调控包括肝癌等疾病的发生，有研究显示其在肝脏组织中与细胞表型调控密切相关。本项目利用NPAS2全身敲除的小鼠和NPAS2高表达及低表达的肝星状细胞系作为实验材料，从体内、体外水平探索及验证了NPAS2调控肝星状细胞活化进而影响肝纤维化进展的机制。结果证实了NPAS2与BMAL1形成异二聚体发挥转录因子作用，直接转录激活Hes1的表达，从而促进肝星状细胞活化，进而促进肝纤维化的进展。其中miR-19b-3p下调可能是肝损伤后NPAS2表达升高的原因。本研究丰富了肝纤维化发生发展过程的机制，为今后对肝纤维化的干预及防治提供了新的思路及实验数据。