肝细胞对维持肝脏功能和稳态起至关重要的作用，但肝细胞损伤对肝纤维化的作用尚未得到足够的重视。FOXA2（HNF3β）系肝细胞核因子家族的重要成员，是维持肝细胞分化和功能的重要转录因子。我们前期研究发现，FOXA2在纤维化肝组织表达明显下调；上调FOXA2表达可显著减轻大鼠肝纤维化；但体外研究显示，FOXA2可促进肝星状细胞（HSCs）活化和增殖。本课题拟以FOXA2为靶点，利用其在肝细胞及HSCs的不同作用，应用多种模式动物和细胞特异性表达载体，分别敲除或过表达肝细胞、HSCs 中FOXA2，观察其表达变化对肝脏不同细胞的作用及肝纤维化的影响，并利用肝细胞特异TGFβ1条件敲除小鼠、基因芯片和miRNA芯片，探讨肝细胞FOXA2对肝脏炎症和纤维化的作用机制。本课题将阐明损伤肝细胞诱导HSCs活化和促进肝纤维化的机制，确定保护肝细胞对肝纤维化的疗效，有望为肝纤维化治疗提供新的思路和方法。

Hepatocytes are critical for the maintenance of liver function and liver homeostasis, but the functional role of impaired hepatocytes in hepatic fibrogenesis remains elusive. FOXA2 (HNF3β), a member of hepatocyte nuclear factors (HNFs) family, plays a key role in hepatocyte differentiation and function maintenance. Our previous study indicated that the expression of FOXA2 was suppressed in fibrotic liver tissues in rats. Up-regulation of FOXA2 markedly alleviated hepatic fibrosis in rats. Nevertheless, overexpression of FOXA2 unexpectedly resulted in the activation and proliferation of hepatic stellate cells (HSCs) in vitro. Based on the distinct role of FOXA2 in hepatic cells, we will investigate the effect of FOXA2 on hepatocyte, HSCs and liver fibrosis using hepatocyte-specific or HSCs-specific conditional knockout mice and expression vectors in this project. Moreover, we will explore the underlining mechanism of inflammation and fibrosis induced by FOXA2 using hepatocyte-specific TGFβ1 conditional knockout mice, gene and miRNA chips. This study will clarify the mechanism regarding the effect of impaired hepatocytes on HSCs activation and liver fibrosis, ascertain the efficacy of restoration of hepatocytes functions in liver fibrosis and provide a novel method for the treatment of liver fibrosis.