肝细胞核因子1α在肝病慢性化和转归中的作用及其分子和细胞机制

It has been known that inflammation is critical for liver injury and the progression of liver diseases. Hepatocyte nuclear factor 1α (HNF1α) is a key member of HNF family which plays a pivotal role in hepatocyte differentiation and function maintenance. Our previous study has demonstrated that the expression of HNF1α was significantly reduced in fibrotic liver. Down-regulation of HNF1α by siRNA notably exacerbated hepatic fibrosis in rats, suggesting that HNF1α plays an indispensable role in hepatic fibrogenesis. The Src domain-containing phosphatase-1 (SHP-1), a protein tyrosine phosphatase, is a well-known inhibitor of inflammatory signaling cascades. Our preliminary data revealed that HNF1α may inhibit the inflammatory activation via the enhanced expression of SHP-1 in liver. In the current study, we will further investigate the effect of HNF1α in hepatic fibrogenesis, and clarify the relationship between SHP-1 and HNF1α and role of SHP-1 in chronic liver injury. In addition, we will identify the signal pathway for the inflammatory suppression by HNF1α and elucidate the molecular mechanism in which HNF1α is decreased in chronic liver injury. Finally, we aim to unravel the crosstalk between hepatocytes and HSCs during the process of liver impairment. Theses findings might elucidates the novel molecular and cellular mechanisms that are responsible for the progression of chronic liver diseases and provide a new strategy and drug targets for the treatment of chronic liver diseases.

目前研究认为，炎症反应对肝损伤和肝病慢性化起至关重要的作用。肝细胞核因子1α（HNF1α）是肝细胞核因子家族的重要成员，对肝细胞分化和功能维持起重要作用。我们前期研究发现，HNF1α在肝纤维化组织中表达下调，利用小干扰RNA降低肝脏HNF1α表达可明显上调肝脏炎症因子表达，并显著加重大鼠肝纤维化，提示HNF1α在肝纤维化发生过程中起重要作用。此外，HNF1α可能通过上调炎症负调节因子SHP-1而抑制肝细胞炎症因子表达。本课题将对HNF1α在肝纤维化发生过程中的作用进行深入研究，确定HNF1α与SHP-1的关系及其在慢性肝病进展中的作用，探讨肝细胞HNF1α下降的机制及其对肝脏炎症相关信号通路的作用，并探索肝损伤过程中肝细胞与肝星状细胞crosstalk及其机制，以揭示肝病慢性化及转归的分子及细胞机制，为临床治疗慢性肝病提供新的治疗策略和药物靶点。

肝细胞核因子1α（HNF1α）是肝细胞核因子家族的重要成员，对肝细胞分化和功能维持起重要作用。我们既往的研究发现HNF1α对肝癌具有抑制作用。本课题研究发现肝细胞核因子HNF1α在人肝纤维化/肝硬化组织和大鼠肝纤维化组织中表达下调；在大鼠肝纤维化模型中，抑制HNF1α表达促进大鼠肝纤维化发生，而过表达HNF1α对大鼠肝纤维化具有显著治疗作用； HNF1α通过结合酪氨酸磷酸酶SHP-1的启动子区促进其转录表达，抑制SHP-1的表达可阻断HNF1α对大鼠肝纤维化的抑制治疗作用；HNF1α通过调控SHP-1降低炎症信号通路NFκB和JAK-STAT在肝细胞中的活化；而NFκB和JAK-STAT通路下游miR-21和miR-146a可通过结合HNF1α 3′UTR下调HNF1α表达，从而证实肝细胞中存在HNF1α/SHP-1/STAT3/p65/miR- 21/miR-146a调控环路，在此环路的影响下HNF1α表达下调可导致肝细胞发生持续的炎症反应；利用原代肝细胞和肝星状细胞共培养实验，明确了肝细胞和肝星状细胞之间由细胞因子IL-6、TNF-α、TGFβ1介导的交互调控作用，揭示了HNF1α下调在肝病慢性化及其转归的分子及细胞机制。我们进一步构建了HNF1α基因条件敲除小鼠，并发现在肝细胞中特异性敲除HNF1α可导致肝细胞炎症信号通路活化，引起肝脏自发脂肪肝和肝纤维化，并最终导致小鼠自发肝癌。我们研究阐明了HNF1α介导的肝细胞炎症信号环路在慢性肝病发生发展过程中的重要作用，有望为临床治疗慢性肝病提供新的治疗策略和药物靶点。