Department of Cardiology and Shanghai Institute for Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
Med Res Rev. 2023 Jan;43(1):5-30. doi: 10.1002/med.21921. Epub 2022 Aug 17.
The endoplasmic reticulum (ER) governs the proper folding of polypeptides and proteins through various chaperones and enzymes residing within the ER organelle. Perturbation in the ER folding process ensues when overwhelmed protein folding exceeds the ER handling capacity, leading to the accumulation of misfolded/unfolded proteins in the ER lumen-a state being referred to as ER stress. In turn, ER stress induces a gamut of signaling cascades, termed as the "unfolded protein response" (UPR) that reinstates the ER homeostasis through a panel of gene expression modulation. This type of UPR is usually deemed "adaptive UPR." However, persistent or unresolved ER stress hyperactivates UPR response, which ultimately, triggers cell death and inflammatory pathways, termed as "maladaptive/terminal UPR." A plethora of evidence indicates that crosstalks between ER stress (maladaptive UPR) and inflammation precipitate obesity pathogenesis. In this regard, the acquisition of the mechanisms linking ER stress to inflammation in obesity might unveil potential remedies to tackle this pathological condition. Herein, we aim to elucidate key mechanisms of ER stress-induced inflammation in the context of obesity and summarize potential therapeutic strategies in the management of obesity through maneuvering ER stress and ER stress-associated inflammation.
内质网 (ER) 通过驻留在 ER 细胞器中的各种伴侣蛋白和酶来控制多肽和蛋白质的正确折叠。当蛋白质折叠超过 ER 处理能力时，ER 折叠过程就会受到干扰，导致错误折叠/未折叠的蛋白质在 ER 腔中积累——这种状态被称为 ER 应激。反过来，ER 应激会诱导一系列信号级联反应，称为“未折叠蛋白反应”(UPR)，通过一系列基因表达调节来恢复 ER 稳态。这种类型的 UPR 通常被认为是“适应性 UPR”。然而，持续或未解决的 ER 应激会过度激活 UPR 反应，最终触发细胞死亡和炎症途径，称为“适应性/终末 UPR”。大量证据表明，ER 应激（适应性 UPR）和炎症之间的串扰促使肥胖症发病。在这方面，了解将 ER 应激与肥胖症炎症联系起来的机制可能揭示出针对这种病理状况的潜在治疗方法。在本文中，我们旨在阐明肥胖症中 ER 应激诱导的炎症的关键机制，并总结通过操纵 ER 应激和 ER 应激相关炎症来管理肥胖症的潜在治疗策略。
