Effect of Arestin Domain-Containing 4 Protein on Glucose Metabolism

项目摘要 Arrestin超家族蛋白控制着反式转运蛋白的运输、周转和信号转导。 膜受体，以及其他细胞内的信号功能。该委员会的几名成员 家族，包括ARRDC3和TXNIP，现已被认为在新陈代谢中发挥重要作用。 ARRDC4是一种在体外被证明抑制葡萄糖摄取的未被研究的蛋白质， 与泛素连接酶相互作用，在膜受体转运中发挥作用。活体内 ARRDC4的功能和分子机制尚不清楚。我的初步实验 与野生型相比，系统缺失ARRDC4的小鼠对胰高血糖素具有抵抗性 控制。肝糖异生和胰高血糖素信号与肝脏缺陷 在ARRDC4KO小鼠的肝组织中也观察到葡萄糖的产生受到抑制。我 我现在已经为这个项目生成了一个新的条件删除ARRDC4鼠标模型。 胰升糖素受体是一种gpr，因此是与arrestin家族相互作用的潜在靶点。 蛋白质。由于ARRDC4与膜蛋白和7TM受体相互作用，是一个重要的目标 我研究的重点是回答ARRDC4是否通过与胰高血糖素相互作用来控制胰高血糖素信号 受体或其下游介体。这个项目的具体目标将集中在解开 ARRDC4在体内肝脏糖代谢中的作用及其机制 在分子水平上的调控。因为ARRDC4本身受葡萄糖和胰岛素的调节， 确定ARRDC4的代谢功能有可能揭示代谢反馈 葡萄糖代谢中的循环，与胰高血糖素信号相互作用。

Project Summary The Arrestin superfamily of proteins controls the trafficking, turnover and signaling of trans- membrane receptors, as well as other intracellular signaling functions. Several members of the family, including ARRDC3 and TXNIP, are now known to have important roles in metabolism. ARRDC4 is an understudied protein that has been shown to inhibit glucose uptake in vitro, interact with ubiquitin ligases and plays a role in membrane receptor trafficking. The in vivo functions and the molecular mechanisms of ARRDC4 are unknown. My preliminary experiments reveal that mice with systemic deletion of ARRDC4 are glucagon resistant compared to wildtype controls. Decreased hepatic gluconeogenesis and glucagon signaling and defects in hepatic glucose production suppression were also observed in the liver tissues of ARRDC4KO mice. I have now generated a new conditional deletion ARRDC4 mouse model for this project. The glucagon receptor is a GPCR, and therefore a potential target to interact with arrestin family proteins. As ARRDC4 interacts with membrane proteins and 7TM receptors, an important goal of my research is to answer if ARRDC4 controls glucagon signaling by interacting with glucagon receptors or its downstream mediators. The specific aims of this project will focus on unraveling the functions of ARRDC4 in hepatic glucose metabolism in vivo and the mechanism of ARRDC4 regulation at the molecular level. Because ARRDC4 is itself regulated by glucose and insulin, defining the metabolic functions of ARRDC4 has the potential to reveal a metabolic feedback loop in glucose metabolism that interfaces with glucagon signaling.