Ubr3调控的新型肝分泌因子在调节糖脂代谢网络中的作用及机制

Certain hepatokines are known to play key roles in systemic regulation of glucose and lipid metabolism by mediating the communication between liver and other organs. It also has been proved that some hepatokines and their corresponding receptors could be regarded as important therapeutic targets. Thus, “Discovering novel hepatokines and disclosing the mechanism how they regulate the systemic glucose and lipid metabolic homeostasis” has been always regarded as one of the most important direction in this field. The applicant has found that knockdown an E3 ligase, Ubr3, in liver could lead to increased appetite and insulin resistance in adipose tissue. This project integrates the methods and techniques of proteomics, molecular biology and cytobiology, and two novel heptokines----Sperinf2 and LCN2 have been found, which might be regulated by Ubr3. The primary in vitro and in vivo experimental results indicate that Serpinf2 could promote the differentiation and maturity of white adipose tissue, and LCN2 might affect the appetite through targeting hypothalamus. For this reason, the aims of the proposal study are to further explore the signaling mechanisms by which Serpinf2 affect the glucose and lipid metabolism in adipose tissue. Moreover, the proposed study will aim to explore the mechanism underlying the effect of LCN2 on appetite and how Ubr3 regulating Sperinf2 and LCN2. Therefore, this project should be useful to develop new strategies of treatment of glucose and lipid metabolic diseases.

肝分泌因子是肝脏与其它器官之间信息交流的重要媒介，是机体糖脂代谢网络调控的关键元件。肝分泌因子及其受体是干预和治疗代谢性疾病的重要药物靶点。因此，“发现新型肝分泌因子并探究其调控糖脂代谢的作用机制”一直是本领域的研究热点。申请人在前期研究中，发现在肝脏中特异性敲低E3连接酶Ubr3的表达后，可以远程促进小鼠食欲的增加以及脂肪组织“胰岛素信号传导”的减弱。通过集成蛋白质组学、分子生物学、细胞生物学等手段，申请人找到两个新颖的肝分泌因子Serpinf2和LCN2。前期的体内和体外初步研究结果，暗示Serpinf2可以促进白色脂肪分化和成熟；LCN2可以靶向下丘脑并影响食欲。本课题拟揭示肝分泌因子Serpinf2和LCN2，分别对脂肪和中枢神经的调控机理，以及Ubr3对两种肝分泌因子的调控机制，进而为研发防止糖脂代谢相关疾病的药物提供重要理论基础。

项目负责人主要研究肝脏分泌因子在糖脂代谢网络调控中的作用。肝脏分泌因子是机体糖脂代谢网络调控的关键元件，也是干预和治疗代谢性疾病的重要药物靶点。在本项目中，项目负责人及其团队聚焦于肝分泌因子Cp对于代谢的调控机制，相关研究成果包括（1）发现Cp-AMPK信号通路调控肝脏脂质代谢机制；（2）发现RIP1不激活下游炎症反应，直接结合胰岛素受体抑制胰岛素信号的机制；（3）发现TGFβ1转录抑制因子YY1，并开发了激活YY1抗糖尿病肾病的小分子（桉脂素，EDN）；（4）发展系统关联方法，开发了通过促脂肪产热抗肥胖的天然小分子贯叶连翘（HPF）和Indirubin；并开发有限水解酶法，发现并证明Dlat是HPF促进产热的直接靶点；（5）XBP1s是缓解内质网应激的关机调控元件，我们发现了XBP1s的泛素化调控机制，并证明抑制XBP1s泛素化降解有助于缓解内质网应激和胰岛素抵抗；（6）揭示了脂肪棕色化促进透明肾癌恶化的病理机制。