FBXW7调节肝脏Fetuin-A蛋白水平的机制研究

Insulin resistance is an important physiological and pathological basis of a variety of metabolic diseases such as obesity and diabetes. People who are obese or diabetic often have higher serum Fetuin-A level, through which to participate in the occurrence of systemic insulin resistance. However, the mechanisms of hepatic Fetuin-A expression are still unclear. Our previous study in this project found that the ubiquitin-mediated protein degradation of liver Fetuin-A is significantly decreased in obese individuals. FBXW7, which is a member of ubiquitin E3 ligases, was further found to be responsible for the degradation of Fetuin-A. Moreover, the function of FBXW7 dropped significantly in obese individuals. Therefore, we consider that the reduction of ubiquitin-mediated Fetuin-A degradation is the key factor to the increased level of serum Fetuin-A. In order to further explore the mechanism for liver Fetuin-A degradation, this project intends to carry out the following research: (1) identify the key sites involved in the combination of FBXW7 and Fetuin-A, clarify the molecular mechanism of FBXW7 in the regulation of Fetuin-A degradation.(2) to investigate which factors and how they regulating the expression and function of FBXW7. This project will be to clarify the molecular mechanism of increasing Fetuin-A protein levels in liver, to provide the theoretical basis for treatment of insulin resistance and metabolic diseases.

胰岛素抵抗是肥胖、糖尿病等代谢性疾病的重要病理生理基础。肥胖和糖尿病患者血清Fetuin-A水平显著增高，参与全身胰岛素抵抗的发生。然而，肝脏Fetuin-A产生增加的机制尚不清楚。本项目组前期研究发现，肥胖个体肝脏Fetuin-A蛋白的泛素化降解明显减少；进一步发现FBXW7为Fetuin-A蛋白降解的E3连接酶，肥胖个体肝脏FBXW7功能显著下降。因此，我们认为肝脏Fetuin-A蛋白的泛素化降解减少是血清Fetuin-A水平增高的关键原因。为进一步探讨肝脏Fetuin-A降解调节机制，本项目拟开展以下研究：（1）确定FBXW7与Fetuin-A结合并发挥作用的关键位点，阐明FBXW7调控Fetuin-A降解的分子机制；（2）探讨调节FBXW7表达和功能的影响因素和机制。本项目研究将阐明肝脏产生Fetuin-A增多的分子机制，为干预胰岛素抵抗、代谢性疾病治疗药物靶点提供理论基础。

肥胖和糖尿病患者血清Fetuin-A水平显著增高，参与全身胰岛素抵抗的发生。本项目组前期研究发现，肥胖个体肝脏Fetuin-A蛋白的泛素化降解明显减少；进一步发现FBXW7为Fetuin-A蛋白降解的E3连接酶，肥胖个体肝脏FBXW7功能显著下降。因此，我们认为肝脏Fetuin-A蛋白的泛素化降解减少是血清Fetuin-A水平增高的关键原因。为进一步探讨肝脏Fetuin-A降解调节机制，本项目拟开展以下研究：（1）确定FBXW7与Fetuin-A结合并发挥作用的关键位点，阐明FBXW7调控Fetuin-A降解的分子机制；（2）探讨调节FBXW7表达对肥胖和糖尿病患者的影响。重要结果:1.FBXW7依赖S305和S309位点降解Fetuin-A；2.人群研究发现FBXW7基因存在p.Ala204Thr突变，该基因突变导致FBXW7不能够泛素化降解Fetuin-A进而引起更为严重的高血糖和胰岛素抵抗。本研究提示在肝脏中激活或上调FBXW7水平可能是改善代谢紊乱的潜在治疗方法，对理解T2DM的病理生物学有重要意义。