白藜芦醇的肠道菌群代谢物通过激活SIRT1信号通路调节脂肪代谢的机制研究

肠道菌群代谢物是膳食营养发挥作用的重要桥梁。白藜芦醇（RSV）是一种存在于葡萄、花生中的多酚类物质，可通过激活SIRT1信号通路调节脂肪代谢，但近年来的研究对RSV直接激活SIRT1的作用提出了质疑。申请人前期研究发现，在肠道菌群的作用下RSV被转化为4-羟基苯乙酸（4-HPA）、4-羟基苯丙酸等代谢物，并在细胞实验中证明了4-HPA改善脂肪代谢的作用。由此提出科学假设：RSV经肠道菌群降解产生的代谢物（4-HPA）通过激活SIRT1信号通路，调节脂肪代谢。本研究拟在高脂小鼠模型上系统评价4-HPA调节脂肪代谢的作用，并利用抗生素处理，探究RSV是否依赖4-HPA改善脂肪代谢；进一步在体内、体外模型中，基于SIRT1信号通路，使用RNA干扰、小分子抑制剂等探究4-HPA调节脂肪氧化及脂肪棕色化的分子机制。研究成果为靶向调控肠道菌群代谢物改善脂肪代谢提供膳食营养干预新方法。

The gut microbial metabolites play a key role in linking dietary nutrients and beneficial effects. Resveratrol, a polyphenol in grapes and peanuts, is shown to improve adipose browning and lipid metabolism through SIRT1 pathway. However, it was recently shown that RSV might not activate SIRT1 directly. Our previous results demonstrate that RSV could be degraded by the gut microbiota to product 4-hydroxyphenylacetic acid (4-HPA) and 3-hydroxyphenylpropionic acid. Furthemore, in vitro 4-HPA improve lipid metabolism. Then we put forward a scientific hypothesis: RSV activates SIRT1 signaling through the gut microbiota metabolites (4-HPA), then improve lipid metabolism. In this project, the beneficial effects of 4-HPA on lipid metabolism will be evaluated in high-fat-diet fed mouse model. Next, antibiotic treatment will be used to verify the protective effect of RSV depend on the 4-HPA. Furthermore, based on the SIRT1 pathway, the molecular mechanism of 4-HPA accelerated fatty acid oxidation and improved adipose browning will be fully elucidated in vitro and in vivo by using molecular biology technique.Our study will provide a new method of dietary nutrition intervention to improve lipid metabolism through targeted modification of the gut microbial metabolites.