中文摘要：

在真核细胞中，内质网是蛋白质合成、折叠、加工及其质量监控的重要场所。当内质网难以承担蛋白折叠的高负荷时则引发内质网应激（ERstress），激活细胞的未折叠蛋白响应（unfoldedproteinresponse，UPR）。细胞通过内质网跨膜蛋白ATF6、PERK和IREl介导的三条极为关键的UPR信号通路，调控下游相关基因的表达，以增强内质网对蛋白折叠的处理能力。因此，UPR通路在细胞的稳态平衡中具有举足轻重的作用，而这一动态过程的调控对于维持机体的正常生理功能至关重要。近来大量研究表明，在哺乳动物中内质网应激与机体的营养感应和糖脂代谢的调控过程密切相关。在肝脏、脂肪、胰岛以及下丘脑等不同的组织器官中，内质网应激均影响代谢通路的调节机制，因此在糖脂代谢紊乱的发生发展中扮演重要的角色。综上所述，进一步深入了解内质网应激引发代谢异常的生理学机制，可以为肥胖、脂肪肝及2型糖尿病等相关代谢性疾病的防治提供新的潜在药物靶点和重要的理论线索。

英文摘要：

In eukaryotic cells, the endoplasmic reticulum （ER） is a crucial site for protein synthesis, fold- ing and quality control. Increased workload of protein folding during ER stress triggers the cellular unfolded protein response （UPR）, and failure of the ER to adapt to ER stress leads to cellular dysfunction and apoptosis. The ER- localized transmembrane proteins ATF6, PERK and IRE1 mediate the three canonical branches of the UPR signal- ing pathways, which coordinately enhance the functional folding capacity of the ER to manage ER stress. Thus, the UPR is of central importance to cellular homeostasis and survival. Emerging evidence has shown that the UPR pathways are closely associated with cellular nutrient-sensing mechanisms as well as glucose and lipid metabolism. ER stress is found to affect key regulatory programs in metabolically active organs including the liver, adipose tis- sues, pancreatic islets and hypothalamus, and it is increasingly recognized as a critical player in the derangement of metabolic homeostasis. Thus, a better understanding of the pathogenic role of the ER stress pathways will offer novel targets for developing therapeutic leads against metabolic diseases such as obesity and type 2 diabetes.