GADD45β对非酒精性脂肪性肝炎的作用及机制研究

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.

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。

非酒精性脂肪性肝病（NAFLD）的疾病谱包括非酒精性肝脂肪变（NAFL）、非酒精性脂肪性肝炎（NASH）、肝硬化和肝细胞癌(HCC)。目前，NAFLD已经对公共健康产生了严峻挑战，缺乏针对性治疗的药物是一个亟待解决的问题。但是，NAFLD的发病机制很复杂，且尚未完全阐释清楚。在NAFLD的多种致病因素中，肝脏脂肪过度沉积被认为是发病的基础，而胰岛素抵抗是导致病情加速的关键因素。在NAFLD的进展过程中，机体响应代谢的变化而导致一系列基因的表达发生上调或者下调，以适应和代偿NAFLD的发展。因此，找到这样差异表达的并且参与胰岛素抵抗和脂质蓄积的关键调控蛋白对于解释NAFLD的发病机制和为NAFLD的药物研发提供新的思路具有重要的科学意义和应用价值。本课题所聚焦的GADD45β是一种应激蛋白，通过参与调控细胞周期阻滞，DNA修复，细胞凋亡和存活等多种生物学反应以维持细胞的稳态。有研究表明，肝脏GADD45β表达发生变化，可以帮助机体适应营养过剩引起的代谢应激。我们在分析NAFLD的临床数据库及检测营养过剩诱导的模型小鼠肝脏，发现GADD45β的表达在NAFLD病人和高脂高果糖饮食诱导的模型小鼠肝脏中均显著下降。继而我们证实了GADD45β可以改善高脂高果糖饮食诱导的高甘油三酯血症和肝脂肪变性，缓解胰岛素抵抗，最后发现HSP72对于GADD45β改善NAFLD的作用至关重要。同时也探索了在NAFLD模型小鼠肝脏中上调的miR-1249-3p，可能通过靶向GADD45β的3’UTR抑制其转录后的翻译过程，可以部分解释GADD45β在NAFLD中下调的原因。综上所述，GADD45β具有改善脂质蓄积和胰岛素抵抗的作用，它在NAFLD患者肝内的减少可能参与了NAFLD的发生发展，而调控GADD45β可以改善NAFLD的部分病理特征，意味着其有望成为NAFLD的新型潜在治疗靶点。