BMP9对肝脏脂肪聚集的影响及其机制研究

项目名称： BMP9对肝脏脂肪聚集的影响及其机制研究

项目编号： No.81500666

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： 贾彦军

作者单位： 重庆医科大学

项目金额： 18万元

中文摘要： 非酒精性脂肪性肝疾病(NAFLD)与胰岛素抵抗等代谢综合征密切相关。BMP9作为肝脏胰岛素敏感样物质，在胰岛素抵抗的发生发展中发挥着重要的作用。然而，关于BMP9与NAFLD的关系及其机制目前国内外尚不见报道。前期结果显示BMP9在脂肪变性肝脏表达降低，BMP9表达升高抑制肝脏脂肪聚集，而BMP9表达抑制促进肝脏脂肪蓄积，提示BMP9与肝脏脂肪聚集有着紧密的关系。因此，本项目通过构建BMP9转基因小鼠、BMP9表达抑制小鼠及饱和脂肪酸诱导的脂肪变性肝细胞模型，体内外证实BMP9在肝脏脂肪聚集中的作用；结合多种同位素示踪技术分析BMP9对肝脏脂肪代谢途径的影响；其次证实BMP9通过受体调节肝脏脂肪蓄积；最后通过检测smad及“non-smad”信号通路关键分子的活性，解析BMP9调节肝脏脂肪聚集的信号转导机制。研究结果将为NAFLD及相关代谢性疾病的预防或治疗提供一定的实验基础及理论支持。

中文关键词： 肥胖；非酒精性脂肪肝；胰岛素抵抗；甘油三酯；脂代谢异常

英文摘要： Non-alcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic or insulin syndrome，such as insulin resistance. Recent investigations have shown that BMP9, proposed as the hepatic insulin-sensitizing substance, plays vital roles in the development of insulin resistance. However，the causal link between BMP9 and NAFLD and the precise mechanism involved are remain to be elucidated. Our latest studies have shown that the mRNA and protein expressions of BMP9 were significantly decreased in the liver of steatosis. Surprisingly, over-expression of BMP9 inhibits the contents of triglycerides in liver and improved the degree of hepatic steatosis，whereas knockdown BMP9 further aggravated the hepatic triglycerides levels. Therefore, BMP9 is of importance in the progress of hepatic steatosis. Thus, the fully roles of BMP9 in the accumulation of hepatic triglycerides in vivo and in vitro were demonstrated by using the BMP9 transgenic mice，knockdown of BMP9 expression in mice and hepacytoes treated with saturated fatty acids. Moreover, the major metabolic pathways of triglycerides in liver were investigated by using several isotope tracers. Then, we sought to demonstrate whether BMP9 regulates the concentration of hepatic triglycerides via its special membrane receptors. Finally, to clarify the intracellular mechanisms involved in the effects of BMP9 on the hepatic triglycerides, the activities of key molecular in both smad and non-smad signaling pathways were detected by western blot in vivo and in vitro. This project is of potential importance in treatment with NAFLD and its related metabolic diseases.

英文关键词： Obesity;Non-alcoholic fatty liver disease ;Insulin resistance;Triglyceride;Dyslipidemia