Shanghai Institute of Cardiovascular Diseases , Department of Cardiology , Zhongshan Hospital , Fudan University , Shanghai , China.
Division of Gastrointestinal and Liver Disease , Department of Medicine , Keck School of Medicine , University of Southern California , Los Angeles , California , USA.
Hepatology. 2023 Feb 1;77(2):619-639. doi: 10.1002/hep.32562. Epub 2022 May 24.
The endoplasmic reticulum (ER) is an intracellular organelle that fosters the correct folding of linear polypeptides and proteins, a process tightly governed by the ER-resident enzymes and chaperones. Failure to shape the proper 3-dimensional architecture of proteins culminates in the accumulation of misfolded or unfolded proteins within the ER, disturbs ER homeostasis, and leads to canonically defined ER stress. Recent studies have elucidated that cellular perturbations, such as lipotoxicity, can also lead to ER stress. In response to ER stress, the unfolded protein response (UPR) is activated to reestablish ER homeostasis ("adaptive UPR"), or, conversely, to provoke cell death when ER stress is overwhelmed and sustained ("maladaptive UPR"). It is well documented that ER stress contributes to the onset and progression of multiple hepatic pathologies including NAFLD, alcohol-associated liver disease, viral hepatitis, liver ischemia, drug toxicity, and liver cancers. Here, we review key studies dealing with the emerging role of ER stress and the UPR in the pathophysiology of liver diseases from cellular, murine, and human models. Specifically, we will summarize current available knowledge on pharmacological and non-pharmacological interventions that may be used to target maladaptive UPR for the treatment of nonmalignant liver diseases.
内质网（ER）是一种细胞内细胞器，促进线性多肽和蛋白质的正确折叠，这一过程受到 ER 驻留酶和伴侣的严格调控。如果不能形成蛋白质的适当三维结构，就会导致错误折叠或未折叠的蛋白质在内质网中积累，破坏内质网的内稳态，并导致经典定义的内质网应激。最近的研究表明，细胞扰动，如脂肪毒性，也会导致内质网应激。为了应对内质网应激，未折叠蛋白反应（UPR）被激活，以恢复内质网的内稳态（“适应性 UPR”），或者当内质网应激被过度和持续触发时，引发细胞死亡（“适应性 UPR”）。有充分的文献记载表明，内质网应激有助于多种肝病理的发生和发展，包括非酒精性脂肪性肝病、酒精性肝病、病毒性肝炎、肝缺血、药物毒性和肝癌。在这里，我们综述了关于内质网应激和 UPR 在肝疾病的细胞、鼠和人体模型中的病理生理学中的新兴作用的关键研究。具体来说，我们将总结目前关于药理学和非药理学干预的可用知识，这些干预可能用于针对适应性 UPR 治疗非恶性肝疾病。
