非酒精性脂肪性肝病（NAFLD）是临床常见的慢性肝病，其发病机制尚未完全明确。本项目组以往发表于J Hepatol等期刊的系列研究发现，高尿酸是引发NAFLD的重要原因；预实验还发现高尿酸刺激显著上调肝细胞miR-92a表达，抑制miR-92a能减轻高尿酸诱导的肝细胞脂变，提示miR-92a极可能是介导高尿酸引发NAFLD的关键分子，但具体下游机制尚不清楚。本项目拟在已有基础上，进一步确定高尿酸调节肝细胞miR-92a表达的时效及量效关系，同时建立miR-92a表达干预技术并结合基因敲除小鼠，分析miR-92a表达变化对高尿酸诱导NAFLD的影响，以及对靶基因KLF2/4、FOXP1、PTEN、DUSP10及其下游参与影响肝脏糖脂代谢相关分子的调节作用，并用表达谱芯片筛选和验证miR-92a新的靶基因及其调节机制。本项目实施将揭示高尿酸引发NAFLD的新机制，并为疾病防治提供新的理论依据。

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, while its pathogenesis has not been fully elucidated. Our previous clinical and experimental studies found that hyperuricemia is closely associated with NAFLD. We also found that uric acid stimulation significantly upregulated miR-92a expression and induced fat accumulation in hepatocytes. The effect of uric acid on fat accumulation could be blocked by miR-92a mimics. These results suggested that miR-92a is very likely to be a key mediator for the effect of uric acid on NAFLD. Current study aims to investigate the regulatory effect of uric acid on miR-92a expression and the downstream mechanisms by which miR-92a mediates the effect of uric acid on NAFLD. The expression of miR-92a will be manipulated both in vivo and in vitro, and the functional consequences of these manipulations on the degree of hepatic steatosis, expressions of miR-92a targets, including KLF2, KLF4, FOXP1, PTEN and DUSP10, and their downstream molecules involved in hepatic glucose and lipid metabolism will be analyzed. The regulatory mechanisms of miR-92a in NAFLD will also be investigated by microarray analysis, followed by qRT-PCR validation and functional analysis. The results of this study will expand our understanding of the molecular mechanisms behind the association between hyperuricemia and NAFLD, and assist in the eventual development of hypouricemic therapy for the disease.