R-spondin1-LGR4 Signaling and Ischemia/Reperfusion Injury in Steatotic Liver

项目摘要 非酒精性脂肪性肝病是一组与脂肪过度堆积相关的疾病 在肝细胞中。肝脏脂肪变性影响了近30%的成年人，并对 美国社会。非酒精性脂肪性肝病增加与损伤或 生理应激，因此是所有医学学科都关心的问题。我们的初步研究确定了一种 新的分子途径和新的细胞机制将长期能量供应耦合到脂肪变性和 受伤。 我们的研究首次表明，富含亮氨酸重复序列的G蛋白的一个成员-- 偶联受体LGR4在肝细胞中表达。R-响应素家族蛋白最近被鉴定为 LGR4的配体。我们的初步数据也表明，R-Spin1是由肝细胞产生的，R-Spin1是由肝细胞产生的。 Spindin1-LGR4信号在肝脏中存在。与经典的G蛋白偶联受体不同 肝脏LGR4通过G蛋白发挥作用，主要通过Wnt/β-catenin信号通路发挥作用。 此外，初步研究表明，雷帕霉素复合体1(MTORC1)在肝脏中的机制靶点 将长期营养状况与R-Spindin1-LGR4的表达结合起来。脂肪变性下调肝脏R- Spindin1/LGR4，使肝组织更容易受到损伤。我们建议研究它的功能 利用细胞生物学和转基因技术对肝脏R-Spin1-LGR4系统进行了研究。完成这项工作 该提案将推进肝脏生理学的一个全新领域，并将为肝脏提供新的见解 受伤。

Project Summary Non-alcoholic fatty liver disease represents a group of conditions associated with excessive lipid accumulation in hepatocytes. Hepatic steatosis affects almost 30% of adults and imposes a major health burden on American society. Non-alcoholic fatty liver disease increases morbidity and mortality associated with injury or physiological stress, and thus is a concern for all medical disciplines. Our preliminary studies have identified a novel molecular pathway and novel cellular mechanisms that couple long-term energy supply to steatosis and injury. Our studies demonstrate for the first time that a member of the leucine-rich repeat-containing G protein- coupled receptors, LGR4, is expressed in hepatocytes. R-spondin family proteins were recently identified as ligands for LGR4. Our preliminary data also indicate that R-spondin1 is produced by hepatocytes and that R- spondin1-LGR4 signaling is present in the liver. Distinct from classical G protein-coupled receptors which act via G proteins, hepatic LGR4 functions mainly through Wnt/β-catenin signaling. Further, preliminary studies indicate that the mechanistic target of rapamycin complex 1 (mTORC1) in liver couples long-term nutrient status to R-spondin1-LGR4 expression. Steatosis down regulates hepatic R- spondin1/LGR4 and renders hepatic tissue more vulnerable to injury. We propose to investigate the function of the hepatic R-spondin1-LGR4 system using cell biological and transgenic techniques. Completion of this proposal will advance a completely new area of hepatic physiology and will provide novel insights into to liver injury.