HECT类泛素连接酶Smurf1在非酒精性脂肪性肝病中的作用及机制研究

Smurf1, a HECT class ubiquitin ligase, is involved in many physiological and pathological processes. Now, no study of Smurf1 and nonalcoholic fatty liver disease (NAFLD) was found. Our previous study confirmed : ① the Smurf1 expression of NAFLD animal model liver increases; ②In vitro study confirmed that Smurf1 affects hepatocyte steatosis; ③Smurf1 up-regulates nuclear sterol regulatory element binding protein-1c (nSREBP-1c)protein and its target genes. In this project, we will : ①To study the effects of Smurf1 gene knockout on mouse NAFLD;②To observe whether Smurf1 competes with Fbw7a for binding nSREBP-1c,which affect nSREBP-1c ubiquitination degradation; ③ To observe whether the Smurf1 affects Fbw7a mRNA level by MDM2-P53-Fbw7a channels; ④ To observe the effect of Smurf1 on the binding capacity between SREBP-1c and its target gene DNA. This project will elucidate the effect of Smurf1 in the pathogenesis of NAFLD, and will reveal the molecular mechanism of Smurf1 regulating nSREBP-1c and its target genes. This project will helps to further clarify future the pathogenesis of NAFLD and to explore new therapeutic strategies for NAFLD.

HECT类泛素连接酶Smurf1参与多种病理生理过程，但迄今未见Smurf1与非酒精性脂肪性肝病（NAFLD）的相关研究。前期研究证实Smurf1①在动物NAFLD肝脏表达增加②体外敲低或高表达影响肝细胞脂肪变性③上调核型固醇调节元件结合蛋白－1c（nSREBP-1c）蛋白及其靶基因。在本项目中我们将研究①Smurf1基因敲除对小鼠NAFLD发病过程的影响②Smurf1是否与Fbw7a竞争结合nSREBP-1c进而抑制Fbw7ɑ介导的nSREBP-1c泛素化降解③Smurf1是否通过小鼠双微体（MDM2）-p53-Fbw7α途径调控Fbw7ɑ转录水平④Smurf1是否影响nSREBP-1c与其靶基因DNA的结合。本项目将明确Smurf1在NAFLD发病过程中的作用，揭示Smurf1调控nSREBP-1c及其靶基因的分子机制，有助于进一步阐明NAFLD的发病机制和探讨NAFLD防治的新方法。

ECT类泛素连接酶Smurf1参与多种病理生理过程，但迄今未见Smurf1与非酒精性脂肪性肝病（NAFLD）的相关研究。我们研究发现:(1)Smurf1基因敲除小鼠肝脏NAFLD减轻，且nSREBP-1c及其靶基因的蛋白及mRNA水平均降低；（2）体外敲低Smurf1的肝细胞脂肪变性减轻，且nSREBP-1c及其靶基因的蛋白及mRNA水平均降低；（3）体外实验发现Smurf1与nSREBP-1c直接结合，并通过Fbw7α促进nSREBP-1c泛素化降解。但Smurf1通过MDM2-P53-Fbw7α 途径调节脂质代谢还有待进一步研究。综上所述，本项目将有助于进一步阐明 NAFLD的发病机制和探讨NAFLD防治的新方法。