非酒精性脂肪性肝炎（NASH）是肝硬化、肝衰竭和肝癌的主要诱因，至今尚无有效治疗措施，仍需对其复杂的病理机制进行深入研究以期获得更为关键的药物靶点，为NASH诊断、治疗提供更优的选择。GADD45β作为环境应激诱导蛋白，调控细胞生长、凋亡等生命活动，也可调控脂代谢、胰岛素抵抗等与NASH发生密切相关的生理过程，但具体作用方式及机制仍未阐明。我们通过对已公布的NASH病例基因表达数据库分析和动物模型中基因表达检测发现GADD45β表达量与NASH呈明显的负相关性，同时也发现GADD45β过表达对脂毒性和胰岛素抵抗具有显著的缓解作用。基于此，本申请拟开展探讨GADD45β在NASH中表达量降低的分子机制和它对脂毒性和胰岛素抵抗这两个关键的NASH发病因素的调节作用及相应分子机制研究。为深入了解NASH的发病机制，基于GADD45β及其下游通路开发新的NASH治疗策略提供有力的科学证据。

Non-alcoholic steatohepatitis (NASH) is recognized as one of the main causes of liver cirrhosis, failure and hepatocellular carcinoma. However, there is no effective drug in clinic. Although there have been several proteins as targets to explore the drug against NASH, the further research on its complex pathophysiological mechanism are still needed to obtain more information of pivotal proteins as optimal therapeutic choices, which may lay a solid scientific foundation in the diagnosis and treatment of NASH. GADD45β as a stress sensor is implicated in cell growth arrest and apoptosis, etc. Recently, it also has been discovered to regulate the lipid metabolism and insulin resistance which are tightly associated with NASH, while the specific role and underlying mechanism are not clarity yet. We found that the expression level of GADD45β was inversely correlated with NASH in Gene Expression Omnibus (GEO) database and this difference also existed in the livers of model mice for NASH compared with normal mice. Additionally, we also found the overexpression of GADD45β can alleviate lipotoxicity and insulin resistance in cell. Therefore, we plan to explore the molecular mechanism underlying low expression of GADD45β in NASH, investigate the potential role of GADD45β in lowing lipotoxicity and relieving insulin resistance and clarify the related molecular mechanism and signal pathway mechanism, which might deepen our understanding of the NASH pathogenesis and provide the reasonable basis for that GADD45β and its downstream factors can develop as potent targets in NASH treatment.