Endoplasmic reticulum stress and liver diseases.
Endoplasmic reticulum stress and liver diseases.
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DOI：
10.1016/j.livres.2019.01.002
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发表时间：
2019-03-01
期刊：
影响因子：
--
通讯作者：
Green, Richard M
中科院分区：
文献类型：
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作者：
Liu, Xiaoying;Green, Richard M
内质网（ER）应激发生时，ER稳态被打乱与积累的未折叠/错误折叠的蛋白质或钙耗尽。未折叠蛋白反应（unfolded protein response，UPR）是内质网应激激活的一种保护性细胞反应，由肌醇需要酶1 α（inositol-requesting enzyme 1alpha，IRE 1 alpha）、PKR样内质网激酶（PKR-like ER kinase，PERK）和转录激活因子6（activating transcription factor 6，ATF 6）信号通路组成。然而，UPR激活也可以诱导细胞死亡后，持续的ER应激。鉴于其合成和其他生物学功能，肝脏易受ER应激的影响。来自人类肝脏样品和动物疾病模型的大量研究已经表明ER应激和UPR信号通路在肝脏疾病的发病机制中起关键作用，包括非酒精性脂肪性肝病、酒精性肝病、α-1抗胰蛋白酶缺乏症、胆汁淤积性肝病、药物诱导的肝损伤、缺血/再灌注损伤、病毒性肝炎和肝细胞癌。广泛的研究已经证实了ER应激诱导的潜在机制和UPR通路在疾病发展过程中的作用。此外，ER应激和UPR蛋白和基因已成为治疗肝脏疾病的新兴治疗靶点。
Endoplasmic reticulum (ER) stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion. The unfolded protein response (UPR), comprising of inositol-requiring enzyme 1alpha (IRE1alpha), PKR-like ER kinase (PERK) and activating transcription factor 6 (ATF6) signaling pathways, is a protective cellular response activated by ER stress. However, UPR activation can also induce cell death upon persistent ER stress. The liver is susceptible to ER stress given its synthetic and other biological functions. Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and UPR signaling pathways in the pathogenesis of liver diseases, including non-alcoholic fatty liver disease, alcoholic liver disease, alpha-1 antitrypsin deficiency, cholestatic liver disease, drug-induced liver injury, ischemia/reperfusion injury, viral hepatitis and hepatocellular carcinoma. Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of UPR pathways during the development of the diseases. Moreover ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.