昆丹优化方通过AMPK-mTOR-ULK1通路调节肝细胞自噬发挥治疗代谢综合征的机制研究

Insulin resistance is the main pathological basis of metabolic syndrome which is the difficult and hot point of clinical treatment and scientific research on endocrine disease now. Researches show that AMPK-mTOR-ULK1-mediated hepatocyte autophagy is very important in the treatment of metabolic syndrome. Our previous research has shown that optimized kun-dan formula could treat metabolic syndrome and regulate the AMPK-mTOR-ULK1 pathway. Based on the above research results, we propose a hypothesis that the protective effect of optimized kun-dan formula on metabolic syndrome may associate with the regulation of the AMPK-mTOR-ULK1 pathway. In our research, insulin-resistant LO2 cell model and high-fat diet-fed rat model of metabolic syndrome will be applied to investigate the protective effect of optimized kun-dan formula on metabolic syndrome and illuminate the impact of optimized kun-dan formula on the AMPK-mTOR-ULK1 pathway. What’s more, in order to further verify the effect of optimized kun-dan formula on the AMPK-mTOR-ULK1 pathway, the activator and inhibitor of autophagy, and RNA interference technique are adopted to block hepatocyte autophagy. The results from our research will clarify the treatment function and underlying mechanism of optimized kun-dan formula on metabolic syndrome, finding a novel treatment strategy for traditional Chinese medicine on the metabolic syndrome.

代谢综合征是以胰岛素抵抗为主要病理基础的一类代谢紊乱性疾病，其是目前内分泌疾病的治疗难点和研究热点。现已证实，AMPK-mTOR-ULK1通路介导肝细胞自噬激活对于代谢综合征的治疗有重要意义。课题组研究发现，昆丹优化方对代谢综合征的疗效确切，并且能调节AMPK-mTOR-ULK1自噬通路。因此，本课题提出“昆丹优化方可能通过调节AMPK-mTOR-ULK1通路激活肝细胞自噬发挥治疗代谢综合征作用”的科学推论。本课题拟采用油酸诱导人LO2肝细胞胰岛素抵抗模型和高脂饮食诱导代谢综合征大鼠模型，研究昆丹优化方对代谢综合征的治疗作用与调控AMPK-mTOR-ULK1自噬通路之间的关系。在此基础上，采用自噬激活剂、抑制剂和RNA干扰技术，进一步验证上述作用机制。该研究成果将阐明昆丹优化方对代谢综合征的治疗作用及机制，为中药治疗代谢综合征作用机理研究提供新的靶点。

代谢综合征是以中心性肥胖、高血糖和高血脂为特征的一类代谢紊乱性疾病。胰岛素抵抗，特别是肝脏胰岛素抵抗，已被逐渐认为是代谢综合征的主要危险因素。现已证实，AMPK-mTOR-ULK1通路介导肝细胞自噬对于代谢综合征的治疗有重要意义。课题组研究发现，昆丹优化方对代谢综合征的疗效确切，并且能调节AMPK-mTOR-ULK1自噬通路。但是昆丹优化方调节AMPK-mTOR-ULK1通路激活肝细胞自噬与治疗代谢综合征之间的关系尚不清楚。因此，本研究采用激光共聚焦、分子生物学、小分子RNA干扰和病毒转染等手段，在油酸诱导胰岛素抵抗LO2细胞模型和高脂饮食诱导代谢综合征动物模型上，发现昆丹优化方可能通过上调AMPK-mTOR-ULK1通路激活肝细胞自噬，从而治疗代谢综合征的作用及机制。我们进一步通过采用自噬激活剂、抑制剂和小分子RNA干扰等技术，抑制或者激活肝细胞自噬，最终证实了昆丹优化方可以通过上调AMPK-mTOR-ULK1通路激活肝细胞自噬发挥治疗代谢综合征的作用。该研究成果将阐明昆丹优化方治疗代谢综合征的作用及机制，也为中药治疗代谢综合征的作用机理研究提供新的靶点。