沉默信息调节蛋白1在盐酸小檗碱改善肝脏糖脂代谢紊乱中的机制研究

Energy surplus is the source of abnormal glucose and lipid metabolism, leading to metabolic syndrome as non-alcoholic fatty liver disease （NAFLD）, threatening human health. Insulin resistance is the initiator of metabolic disorder in NAFLD. The safe and effective pharmacologic therapy is still awaiting discovery. Silent information regulator1 （SIRT1） is extensively involved in a variety of biological effects. Our previous study revealed that berberine（BBR）can ameliorate hepatic steatosis by promoting autophagy and inducing the expression of microsomal triglyceride transfer protein in liver. We found SIRT1 also mediates BBR’s effect on improving glucose metabolism. With further investigation, our data showed that BBR inhibited the phosphorylation of glycogen synthase kinases （GSK）in liver, which required SIRT1 as well. Thus, we speculated that BBR regulated the pathways in glucose metabolism related to GSK through SIRT1 in liver. To verify this assumption, our study aims to further discuss the role of SIRT1 in the regulatory mechanism of BBR under its improvement on lipid and glucose metabolism, which will offer a novel theoretical basis for BBR in preventing NAFLD and other metabolic diseases.

非酒精性脂肪性肝病（NAFLD）等代谢综合征呈现出全球化流行趋势，有效治疗这类疾病的药物仍有待发掘。沉默信息调节蛋白1（SIRT1）作为一种去乙酰化酶，广泛参与细胞多种生理活动中。申请人课题组前期研究表明盐酸小檗碱（BBR）可以通过促进自噬、上调微粒体甘油三酯转运蛋白表达等途径缓解能量过剩引起的肝脂沉积。同时初步证实BBR可以改善代谢综合征机体的葡萄糖耐量水平，并发现这一作用有赖于肝脏SIRT1，提示BBR可SIRT1依赖性的改善机体糖代谢紊乱。通过分子生物学研究我们还发现BBR可抑制肝脏糖原合成酶激酶（GSK）磷酸化，这一作用也有赖于SIRT1，我们因此推测BBR可能通过SIRT1改变GSK相关肝脏糖代谢信号通路的激活水平，发挥其改善糖代谢紊乱的作用。为证实这一推测，本项目拟通过体内和体外层面探讨SIRT1在BBR改善肝脏糖脂代谢紊乱中的机制，为BBR治疗代谢性疾病提供新的理论依据。

能量过剩增加了非酒精性脂肪性肝病（nonalcoholic fatty liver disease， NAFLD）等代谢性疾病的患病风险，使得该疾病成为全球范围内最常见的肝脏疾病之一。小檗碱（berberine, BBR）从中药黄连里提取所得，有调节糖脂代谢紊乱的作用，可以显著改善NAFLD。申请人课题组前期研究发现SIRT1部分介导了BBR缓解高能量饮食所致的脂质代谢紊乱作用，其中包括参与BBR对肝细胞自噬的调节和促进白色脂肪棕色化等方面。并发现BBR可以调节肝脏糖原合成酶激酶3β（glycogen synthase kinase 3β , GSK3β）的磷酸化水平。本课题项目通过体内和体外实验，进一步探究BBR改善NAFLD肝脏糖脂代谢紊乱的具体分子机制，发现其中包括BBR对AKT-GSK通路的调控，及SIRT1在这一过程中重要的介导作用。同时发现BBR可以通过对肝细胞铁死亡水平的调节进而改善肝细胞脂质变，我们进一步探索其中可能的分子机制，研究结果示GSK3β磷酸化部分介导了BBR对铁死亡相关通路的调控。本课题研究为BBR改善NAFLD机体代谢紊乱提供新的理论依据。