高果糖摄入导致肝脏尿酸代谢紊乱并促进非酒精性脂肪性肝病的机制研究

非酒精性脂肪性肝病（NAFLD）是临床常见且危害巨大的慢性肝病，其发病机制尚未完全明确。肝脏是果糖代谢和尿酸生成的主要器官，已有研究证实高果糖摄入显著增加肝脏尿酸生成并升高NAFLD发病风险。本团队前期系列研究发现高尿酸是引发NAFLD的重要原因。然而，高果糖摄入如何导致肝脏尿酸代谢紊乱并促进NAFLD发生发展仍不清楚。本项目拟在已有基础上，建立高果糖诱导的NAFLD细胞和小鼠模型并结合基因敲除小鼠，深入揭示高果糖如何通过果糖代谢关键酶KHK与尿酸合成限速酶XO依赖途径调节肝脏尿酸代谢，并进一步揭示高尿酸对ChREBP与SREBP1c及其下游的ACC1、FAS、SCD1等脂肪酸合成关键分子的影响，对NADPH氧化酶及ROS生成和NLRP3炎症小体激活的影响，对MCP-1表达和肝脏巨噬细胞浸润的调控作用。本项目预期结果将从尿酸代谢角度揭示高果糖引发NAFLD的新机制，为疾病防治提供新思路。

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disease with significant clinical importance. The pathogenesis of NAFLD remains unclear. Liver is the major organ involved in fructose metabolism and uric acid production. Recent literatures have repeatedly reported that high fructose consumption significantly increased risk of NAFLD, accompanied with increased hepatic uric acid production, which resulted in hyperuricemia. We previously found that hyperuricemia is a major pathogenic factor for NAFLD, based on the evidence that hyperuricemia directly induced hepatocyte fat accumulation both in vitro and in vivo. However, the regulatory mechanisms of high fructose consumption on hepatic uric acid metabolism and NAFLD remains poorly understood. In this study, we are going to establish high-fructose induced cellular and mouse models of NAFLD, as well as gene knockout mouse models. The interactions between hepatic fructose metabolism and uric acid production will be investigated by means of manipulation of the key enzymes fructokinase and xanthine oxidase. The regulatory effects of uric acid on the expressions of transcription factors ChREBP and SREBP1c, and their downstream genes involved in de novo lipogenesis including ACC1, FAS, and SCD1 will be investigated. The regulatory effects of uric acid on NADPH oxidase, ROS production, NLRP3 inflammasome activation, as well as the regulatory role of uric acid on hepatic MCP-1 expression and macrophage infiltration will also be studied. The results of this study will expand our understanding of the mechanisms by which high fructose consumption induces hyperuricemia and NAFLD, and may help the development of novel therapeutics for NAFLD.