SUV39H1调控非酒精性脂肪性肝炎的表观遗传机制研究

项目名称： SUV39H1调控非酒精性脂肪性肝炎的表观遗传机制研究

项目编号： No.81500441

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 许慧慧

作者单位： 南京医科大学

项目金额： 18万元

中文摘要： 随着我国居民饮食结构的西化以及多坐少动生活方式的流行，与肥胖症相关的脂肪性肝炎（NASH）发病率显著上升。近年来的研究认为，表观遗传机器是联系营养过剩引起的机体应激与代谢系统疾病的重要桥梁。SUV39H1是真核生物中唯一的组蛋白H3K9三甲基转移酶，与基因转录抑制密切相关。但对于SUV39H1是否参与调控脂肪性肝炎国内外还没有类似的报道。我们的前期实验发现，SUV39H1在肝细胞中抑制SIRT1基因转录；相反，抑制SUV39H1活性显著下调游离脂肪酸诱导的炎症介质合成。SIRT1属于Sirtuin家族，具有强烈的抗炎、抗氧化应激、促进能量消耗的性质。因此，我们提出假说，SUV39H1在营养应激信号作用下，改变肝细胞中的NASH相关基因表达（如SIRT1），从而促进脂肪性肝炎的发生发展。我们希望通过这一研究，揭示调控脂肪性肝炎新的表观遗传机制，并为临床治疗脂肪性肝炎提供新的靶点。

中文关键词： 非酒精性脂肪性肝炎；组蛋白甲基转移酶；表观遗传学；转录调控；代谢稳态

英文摘要： Changes in diets and life styles in China accompany an increase in the prevalence of non-alcoholic steatohepatitis (NASH) associated with obesity. Recent research has provided ample evidence that the epigenetic machinery is a key bridge linking nutrition surplus-induced body stress and metabolic disorders. SUV39H1 is the sole histone H3K9 trimethyltransferase in eukaryotes and plays a crucial role in transcriptional repression. Our preliminary data suggest that over-expression of SUV39H1 in hepatocyte represses the transcription of SIRT1 while pharmaceutical inhibition of SUV39H1 activity attenuates the transcription of pro-inflammatory mediators induced by free fatty acids. SIRT1 is a member of the Sirtuin family with known characteristics of anti-inflammation, anti-oxidative stress, and pro-energy expenditure. Therfore, we hypothesize that under the stimulation of nutrient surplus, SUV39H1 alters the transcription of genes involved in NASH (e.g., SIRT1) in hepatocyte to promote the pathogenesis of steatohepatitis. We hope to unveil a new epigenetic mechanism accounting for NASH pathogenesis while at the same time providing a new druggable target for NASH intervention.

英文关键词： non-alcoholic steatohepatitis ;SUV39H1;epigenetics;transcriptional regulation;metabolic homeostasis