酒精性脂肪肝发生中受损肝干细胞分化特性的研究

Alcoholic fatty liver disease (AFLD) is a metabolic disorder syndrome caused by chronic alcoholism. The principal therapy for AFLD is abstinence, even though the fatty liver cannot revert to normal in many cases after abstinence. Our previous research found that alcohol can significantly affect differentiation of the hepatic stem cells (HepSCs). Considering HepSCs are the basis of liver homeostasis maintenance, we proposed a biological hypothesis to explaining the reasons of refractory AFLD. Long-term alcohol abuse damages hepatocytes which leading to disorder of lipid metabolism. Moreover, alcohol-injured HepSCs that result to ‘permanent damage’ in many functional genes (i.e., lipid metabolism), thus the progeny cells of HepSCs also carry mutation genes which result in abnormal lipid metabolism. This hypothesis may explain the irreversible injury of alcoholic hepatitis even after abstinence. In this project, we plan to isolate HepSCs and its progeny via FACS during the process of AFLD based on the HepSCs lineage tracing mouse strain that we established previously, and examine the DNA damage and related gene expression to investigate the mechanism of HepSCs injury caused by alcohol and the disorder of lipid metabolism in progeny cells. In our project, the research target of AFLD is expanded from the hepatocyte to it origin cell—hepatic stem cells, which may facilitate the development of new therapeutic method for prevention and control of AFLD.

酒精性脂肪肝（AFLD）是因长期饮酒引起肝脂肪变性的代谢紊乱综合症，大多患者戒酒后仍然不能完全逆转。申请人前期研究发现酒精可明显影响肝干细胞（HepSCs）的分化特性，结合“HepSCs是肝脏稳态维持的结构基础”这一生物学特性，提出AFLD临床难愈性的细胞生物学基础的科学假说：长期饮酒可损伤成熟肝细胞导致脂代谢紊乱，同时也可诱发HepSCs脂代谢相关基因的突变（即“永久性”损伤），使其后裔细胞（成熟肝细胞）亦表现脂代谢异常，由此导致AFLD患者在戒酒后其肝功能仍不能完全恢复。本项目基于前期建立的HepSCs谱系示踪小鼠拟制备AFLD模型，在AFLD病程中，采用FACS技术在不同时间点分离HepSCs及其后裔细胞，动态地探讨酒精对HepSCs的损伤作用及其后裔细胞脂代谢功能异常的机制。本研究将AFLD的研究靶标从传统的成熟肝细胞扩展至肝干细胞层面，力争为AFLD防治手段的研究发现新的突破点。