Nesfatin-1在胃X/A样细胞mTOR信号通路调控肝脏脂代谢中的作用和机制

代谢相关脂肪性肝病是终末期肝病的重要病因，目前治疗手段有限，亟需寻找新的治疗靶点。前期研究显示，胃X/A样细胞mTOR信号通路可部分通过胃饥饿素调控肝脏脂代谢。Nesfatin-1与胃饥饿素同为X/A样细胞分泌，但功能截然相反，其是否参与X/A样细胞mTOR信号通路对肝脏脂代谢的调控尚不清楚。前期发现，胃X/A样细胞mTOR信号通路调节Nesfatin-1的合成、分泌，且Nesfatin-1上调肝原代细胞的AMPK磷酸化水平。基于此，我们拟：利用胃X/A样细胞mTOR失活或激活的基因敲除小鼠，外源性给予Nesfatin-1或其中和抗体，探明Nesfatin-1在X/A样细胞mTOR信号通路调控肝脏脂代谢中的作用；体外分离培养肝原代细胞，利用AMPK抑制剂或siRNA，探讨Nesfatin-1发挥作用的分子机制。本研究可完善胃-肝脏对话机制，并为从消化道防治代谢相关脂肪性肝病提供新靶点。

Metabolic associated fatty liver disease (MAFLD), which is the most common cause of end-stage liver disease such as cirrhosis and liver cancer, increases the risk of type 2 diabetes, atherosclerosis and other diseases, and affects the health of Chinese people. It is urgent to find new therapeutic targets, because treatment of MAFLD is still limited due to the undefined pathogenesis. Our previous study shows mTOR signaling in gastric X/A-like cells contributes to lipid metabolism partially through regulating ghrelin synthesis and secretion. Nesfatin-1 and ghrelin, synthesized and secreted by gastric X/A-like cells, have almost opposite functions. Whether nesfatin-1 acts in the regulation of hepatic lipid metabolism by mTOR signaling in gastric X/A-like cells remains unknown. We found that nesfatin-1 synthesis and secretion were regulated by mTOR signaling in gastric X/A-like cells, and nesfatin-1 increased levels of AMPK phosphorylation in cultured hepatocytes. Based on these observations, we propose to (1) use conditional knockout mouse models with inactivated or activated mTOR signaling in gastric X/A-like cells, and reverse intervention by continuous peripheral infusion of nesfatin-1 or nesfatin-1 neutralizing antibody to examine the role of nesfatin-1 in the regulation of hepatic lipid metabolism by mTOR signaling in gastric X/A-like cells; (2) use cultured hepatocytes to validate the effect of nesfatin-1 and explore its mechanism through AMPK inhibitors or siRNA. The result of this project will enrich the mechanism of gut-liver crosstalk, provide novel strategies and targets for the prevention and treatment of MAFLD.