Effect of Arestin Domain-Containing 4 Protein on Glucose Metabolism

项目摘要 Arrestin蛋白超家族控制着跨- 膜受体，以及其他细胞内信号传导功能。的几名成员 目前已知ARRDC 3和TXNIP家族在代谢中具有重要作用。 ARRDC 4是一种研究不足的蛋白质，已显示其在体外抑制葡萄糖摄取， 与泛素连接酶相互作用，并在膜受体运输中起作用。体内 ARRDC 4的功能和分子机制尚不清楚。我的初步实验 显示与野生型相比，具有ARRDC 4系统性缺失的小鼠是胰高血糖素抗性的 对照肝细胞生成和胰高血糖素信号传导减少， 在ARRDC 4KO小鼠的肝组织中也观察到葡萄糖产生抑制。我 现在已经为这个项目生成了一个新的条件删除ARRDC 4小鼠模型。 胰高血糖素受体是GPCR，因此是与arrestin家族相互作用的潜在靶点 proteins.由于ARRDC 4与膜蛋白和7 TM受体相互作用， 我的研究的一个目的是回答ARRDC 4是否通过与胰高血糖素相互作用来控制胰高血糖素信号传导 受体或其下游介质。该项目的具体目标将集中在解开 ARRDC 4在体内肝脏葡萄糖代谢中的作用及其机制 在分子水平上的调节。因为ARRDC 4本身受葡萄糖和胰岛素调节， 确定ARRDC 4的代谢功能有可能揭示代谢反馈 葡萄糖代谢中与胰高血糖素信号传导相互作用的环。

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.