HLF在肝纤维化中的作用及机制研究

Liver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing the functional parenchyma with scar tissues, which ultimately leads to cirrhosis, liver failure, and even hepatocellular carcinoma. But as yet, no anti-fibrotic therapy has been approved for liver fibrosis, which thus emphasizes the urgency of clarifying the detailed mechanism of liver fibrosis and identifying novel therapeutic targets for effective intervention. We have previously discovered that the expression of HLF (Hepatic leukemia factor) was absent in normal human and murine livers and was only detected in activated HSCs (hepatic stellate cells) of fibrotic livers. Moreover, the mutation deletion of HLF impaired HSC activation and attenuated liver fibrosis in mice. Preliminary mechanistic study revealed that upregulated HLF could promote HSC activation and liver fibrosis via IL-6/STAT3 signaling. In this project, we plan to investigate the role of HLF in HSC activation and liver fibrosis, as well as the underlying mechanism utilizing HLF HSC-specific knockout mice model, primary HSCs and HLF siRNA encapsulated in VitaminA-coupled liposomes, and then to evaluate the feasibility of using HLF as an HSC-specific intervention target in anti-fibrotic therapy.

肝纤维化早期发病隐匿，到了进展期严重的疤痕反应会破坏肝脏的结构和功能，最终可能导致肝硬化、肝衰竭，甚至肝癌。目前还没有被批准用于肝纤维化的治疗方案，因此进一步研究肝纤维化的发病机制、寻找新的特异性干预靶点非常重要。本项目前期通过对临床样本的分析发现，HLF（肝白血病因子）在正常肝脏中几乎不表达，而在纤维化肝脏中表达明显升高，定位于活化的HSCs（肝星状细胞）；突变敲除小鼠HLF基因可以抑制HSCs活化和肝纤维化；机制研究提示HLF可能通过调控IL-6/STAT3通路促进了HSCs活化和肝纤维化。本项目拟利用HLF突变敲除和HSCs中特异敲除的小鼠肝纤维化模型、原代HSCs模型及肝纤维化治疗模型等，深入研究HLF在HSCs活化和肝纤维化中的作用及机制，评价HLF作为HSCs特异性干预靶点在肝纤维化治疗中的应用价值。本项目的实施可望为肝纤维化发病机制提供新的理论，并为肝纤维化治疗提供新的思路。

肝纤维化早期发病隐匿，到了进展期严重的疤痕反应会破坏肝脏的结构和功能，最终可能导致肝硬化、肝衰竭，甚至肝癌。目前还没有被批准用于肝纤维化的治疗方案，因此进一步研究肝纤维化的发病机制、寻找新的特异性干预靶点非常重要。本项目在前期研究的基础上，通过HLF（肝白血病因子）突变敲除小鼠肝纤维化模型，探究了HLF在肝纤维化中的作用；利用原代HSCs（肝星状细胞）模型、HSC细胞株及肝纤维化临床样本，明确了HLF对HSCs活化的调控及机制。本项目通过对临床样本的分析发现，HLF在正常肝脏中几乎不表达，而在纤维化肝脏中表达明显升高，定位于活化的HSCs（；突变敲除小鼠HLF基因可以抑制HSCs活化和肝纤维化，提示HLF是一个新的功能性、特异性的活化HSCs标志物；机制研究发现HLF/IL-6/STAT3正反馈信号通路促进了肝星状细胞活化和肝纤维化。本项目的发现不但加深了我们对肝纤维化发病机制的理解，更表明HLF作为肝星状细胞特异性干预靶点在肝纤维化治疗中有重要的应用价值，为肝纤维化发病机制提供了新的理论，并为肝纤维化治疗提供了新的思路。