Menin在非酒精性脂肪肝所致肝脏纤维化进程中的作用机制及干预研究

Along with the continuous increase of the prevalence of nonalcoholic fatty liver disease (NAFLD), liver fibrosis induced by nonalcoholic fatty liver has become an important clinical problem. Mechanisms and regulations of cellular components and related genes, which play key roles in liver fibrosis induced by NAFLD, have become new research focuses in the field of hepatic fibrosis. Our research group is committed to studies regarding the regulatory mechanisms of liver metabolic homeostasis in a long history, by use of hepatocyte-specific MEN1 knockout mice, finding that MEN1 gene plays a pivotal role in the progress of hepatic steatosis caused by the imbalance of aging and metabolic disturbances, and is closely connected with liver fibrosis. Additionally, berberine can also reverse hepatic fatty degeneration. On this basis, our research group will generate hepatocyte-specific MEN1 overexpressed and hepatic stellate cell-specific Men1 transgenic mice and continue to explore the precise functions and regulatory mechanisms of the menin protein encoded by MEN1 gene and related complexes in liver fibrosis, and study their exact roles in hepatocytes and hepatic stellate cells, and then further elaborate the mechanisms of the regulatory network, which influenced the functions of hepatocytes and hepatic stellate cells. In addition, our studies aim to clarify the effects and mechanisms of Chinese medicine berberine in the reversion of liver fibrosis in mice. Finally, our researches will establish innovative and more effectively preventive approaches, diagnostic markers as well as therapeutic targets, and provide scientific evidence for preventing and slowing the progression of hepatic fibrosis induced by NAFLD.

随着非酒精性脂肪肝（NAFLD）患病率不断增高，NAFLD所致肝脏纤维化已成为重要临床问题。调控NAFLD所致肝脏纤维化进程中发挥关键作用的细胞组分及其作用机制已成为新的关注热点。课题组长期致力于肝脏代谢稳态的调控机制研究，利用肝细胞特异性Men1敲除小鼠模型，发现Men1基因在衰老与代谢失衡所致肝脏脂肪变性进展中发挥重要作用且与肝脏纤维化密切联系，并发现小檗碱可逆转脂肪肝变性。在此基础上，课题组将建立肝细胞特异性Men1过表达与肝星状细胞特异性Men1转基因小鼠模型，深入探索Men1基因编码的menin蛋白及相关复合体成员在肝脏纤维化中的精确功能与调控机制，进一步阐述影响肝细胞与肝星状细胞功能的调控网络机制，阐明中药小檗碱在逆转肝脏纤维化中的作用及机制，最终提供新的更有效的肝脏纤维化预防途径、诊断标志物与治疗靶点，为预防和延缓NAFLD所致肝脏纤维化进程提供科学依据。

随着非酒精性脂肪肝（NAFLD）患病率不断增高，NAFLD所致肝脏纤维化已成为重要临床问题。调控NAFLD所致肝脏纤维化进程中发挥关键作用的细胞组分及其作用机制已成为新的关注热点。本项目基于人体与小鼠脂肪肝和肝脏纤维化的组织与模型中观察menin蛋白的动态变化，建立了肝细胞特异性敲除menin小鼠模型，发现Men1基因在衰老与代谢失衡所致肝脏脂肪变性进展中发挥重要作用且与肝脏纤维化密切联系。利用条件性转基因动物模型，细胞系和多种研究技术平台，研究肝脏纤维化过程中menin蛋白在肝脏细胞组分中发挥的不同作用；阐述menin蛋白及其复合体成员在此过程中对特异靶基因和信号通路的调控机制；研究microRNA等上游因素对menin蛋白的影响，揭示内外界因素作用下menin蛋白及复合体通过靶基因调控与信号通路组成的调控网络在肝脏纤维化过程中的关键作用；进一步利用特色的小檗碱药物在已有的脂肪肝和肝脏纤维化人群中进行临床治疗研究，寻找防治肝脏纤维化的新靶点和新疗法。