高血脂症通过诱导BAF60a抑制小鼠肝脏尿素合成进程的分子机制研究

The blood levels of ammonia in mammals are precisely controlled, thus sufficient ammonia is provided in the body to synthesize essential chemicals such as proteins, while ammonia toxicity is avoided. Of note, hepatic ureagenesis plays an important role in the regulation of ammonia homeostasis. Recent studies have indicated that a mouse model with non-alcoholic fatty liver disease and hyperlipidemia demonstrated impaired urea cycle and hyperammonemia. However, the molecualr mechanism through which hyperlipidemia and urea synthesis disturbance are connected remians unclear. On the other hand, BAF60a, a member of SWI/SNF chromatin remodeling complex family, has been shown to regulate various hepatic metabolic processes in response to nutritional signals. In our preliminary study, we found that BAF60a inhibited the promoter transcriptional activity and expression levels of Cps1, a rate-limiting enzyme in hepatic ureagenesis. In the present study, we will elucidate the role of BAF60a in the regulation of hepatic ureagenesis by using high-fat diet-fed hyperlipidemic mouse model and free fatty acids-stimulated primary hepatocytes. Our study will enrich current understandings towards hepatic ureagenesis and ammonia homeostasis, and will also provide a new drug target for the therapy of diseases related to hyperlipidemia-induced ammonia disturbance.

哺乳动物体内的血氨水平受到精准控制，从而保证充足的氨供给用于机体合成蛋白等基本化合物，又不会造成氨毒性。在血氨动态平衡的调节过程中，肝脏的尿素合成途径起着重要作用。近年来研究发现，在非酒精性脂肪肝合并高血脂症动物体内，尿素循环受损，血氨浓度明显升高。然而，高血脂症与尿素合成紊乱之间的分子关联机制尚不清楚。另一方面，染色质重塑复合物SWI/SNF家族成员BAF60a可以响应营养信号，参与调控肝脏多种能量代谢进程。我们在前期研究中发现，BAF60a能抑制肝细胞尿素合成限速酶Cps1的启动子转录活性及表达水平。在本项目中，我们将在体内体外两个层面开展研究，阐明在高脂饲料喂养导致的小鼠高血脂症及体外游离脂肪酸刺激状态下，BAF60a对肝脏尿素合成过程的调节作用，并探讨其中的分子机制。我们的研究将丰富现有的肝脏尿素合成及机体血氨稳态平衡理论，并为治疗高血脂导致的血氨紊乱相关疾病提供新的药物作用靶点。