内质网应激感应分子IRE1α的代谢性激活在代谢稳态中的调控作用与机制

The endoplasmic reticulum (ER) stress is highly associated with the pathogenic progression of obesity and related metabolic disorders. The ER-localized transmembrane signal transducer IRE1 possesses both protein Ser/Thr kinase and endoribonuclease activities, and as the most ancient ER stress sensor, it employs multiple mechanisms to cope with ER stress and govern the cell fate decision. We previously found that mammalian hepatocyte IRE1α is coupled to GPCR-PKA signaling and can be directly phosphorylated at Ser724 within the activation loop of its kinase domain in response to glucagon stimulation during starvation, which in turn is implicated in the control of the gluconeogenic program in the liver. Thus, we propose herein that PKA-directed metabolic activation of IRE1α plays distinct roles in different metabolic tissues such as the adipose and liver. Utilizing the mouse model in which the Ser724 residue is replaced by Ala in the Ern1 gene encoding IRE1α, we aim to investigate how metabolically activated IRE1α exerts its dynamic regulatory effects in adipose issues and in the liver. We also attempt to uncover the molecular features and modes of action of hyperactivated IRE1α during overnutrition in disrupting the homeostatic mechanisms in metabolic remodeling. These studies will not only provide new insights into how IRE1α links metabolic ER stress to the pathogenesis of obesity, diabetes and fatty liver disease, but also offer novel therapeutic targets in proof-of-concept for combatting these devastating metabolic diseases.

内质网应激与肥胖、糖脂代谢紊乱密切相关。内质网跨膜蛋白IRE1α具有蛋白激酶与核糖核酸内切酶的活性，是应对内质网应激的关键信号转导分子。我们前期研究发现，肝脏中IRE1α通过GPCR信号通路可由PKA激酶直接使其Ser724位点发生磷酸化，进而参与糖异生调控；而其过度激活则促进糖脂代谢紊乱的发生发展。由此我们设想，PKA介导的IRE1α磷酸化导致其代谢性激活，在不同组织中可能发挥不同的代谢重塑调节效应。本项目利用基因敲入突变的Ern1α-S724A/S724A小鼠模型和原代细胞系统，探索代谢性激活的IRE1α在脂肪及肝脏等组织中如何参与糖脂代谢重塑的生理学调控过程，解析过度激活的IRE1α促进代谢异常发生的作用模式。本项研究有助于全面了解IRE1α通路在代谢稳态中的动态调节机制，为有效逆转代谢紊乱提供新的分子靶标和原理验证。

内质网应激与肥胖、糖脂代谢紊乱密切相关。感应内质网应激的跨膜蛋白IRE1α具有蛋白激酶与核糖核酸内切酶的活性，是应对代谢应激的关键信号转导分子。本项目利用基因敲入突变的Ern1S724A/S724A小鼠模型、原代细胞系统以及脂肪细胞特异性敲除IRE1α的小鼠模型，以脂肪和肝脏等代谢组织为主要入手点，发现IRE1α的Ser724位点磷酸化控制其激酶与RNA内切酶的激活状态并限制内质网应激诱导的肝脏脂肪变性，解析了脂肪细胞IRE1α通过PGC1α的mRNA降解限制机体产热促进肥胖与代谢紊乱发生发展的作用，揭示了IRE1α代谢性激活调节脂肪组织脂解和棕色化重构的作用机制，为全面了解IRE1α在促进代谢疾病发生发展中的病理生理学基础提供了重要的理论线索及靶标的原理验证。