Endoplasmic reticulum stress in liver disease.
Endoplasmic reticulum stress in liver disease.
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DOI：
10.1016/j.jhep.2010.11.005
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发表时间：
2011-04
影响因子：
25.7
通讯作者：
Kaufman, Randal J.
中科院分区：
文献类型：
--
作者：
Malhi, Harmeet;Kaufman, Randal J.
未折叠蛋白反应（UPR）在内质网（ER）中错误折叠蛋白积累时被激活，其由结合免疫球蛋白蛋白（BiP）/葡萄糖调节蛋白78（GRP 78）感测。未折叠蛋白的积累隔离BiP，因此它从三个ER-跨膜转导物解离，导致其活化。这些转换器是肌醇需要（IRE）1α，PKR样ER激酶（PERK）和激活转录因子（ATF）6α。PERK磷酸化真核起始因子2 α（eIF 2 α），导致整体mRNA翻译减弱，同时选择性增加几种mRNA的翻译，包括转录因子ATF 4及其下游靶点CHOP。IRE 1 α具有激酶和核糖核酸内切酶（RNase）活性。IRE 1 α自身磷酸化激活RNase活性以切割XBP 1 mRNA，产生活性转录因子sXBP 1。IRE 1 α激活还募集并激活应激激酶JNK。ATF 6 α转运到高尔基体，在高尔基体中通过膜内蛋白水解裂解，产生可溶性活性转录因子。这些UPR途径协同作用以增加ER含量，扩大ER蛋白折叠能力，降解错误折叠的蛋白，并减少进入ER的新蛋白的负荷。所有这些都是为了适应解决蛋白质折叠缺陷。面对持续的内质网应激，适应开始失败，细胞凋亡发生，可能通过钙扰动，活性氧和促凋亡转录因子CHOP介导。UPR在几种肝脏疾病中被激活;包括肥胖相关的脂肪肝疾病、病毒性肝炎和酒精诱导的肝损伤，所有这些都与脂肪变性相关，提高了ER应激依赖性脂质稳态改变是脂肪变性基础机制的可能性。肝细胞凋亡是几种肝脏疾病的致病事件，可能与未解决的ER应激有关。如果这是真的，ER应激诱导的细胞死亡之前，ER稳态的恢复可能会提供这些疾病的治疗原理。在这里，我们讨论每个分支的普遍定期审议和他们如何可能影响肝细胞功能在不同的病理状态。
The unfolded protein response (UPR) is activated upon the accumulation of misfolded proteins in the endoplasmic reticulum (ER), that are sensed by the binding immunoglobulin protein (BiP)/glucose-regulated protein 78 (GRP78). The accumulation of unfolded proteins sequesters BiP so it dissociates from three ER-transmembrane transducers leading to their activation. These transducers are inositol requiring (IRE) 1α, PKR-like ER kinase (PERK) and activating transcription factor (ATF) 6α. PERK phosphorylates eukaryotic initiation factor 2 alpha (eIF2α) resulting in global mRNA translation attenuation, and concurrently selectively increases the translation of several mRNAs, including the transcription factor ATF4, and its downstream target CHOP. IRE1α has kinase and endoribonuclease (RNase) activities. IRE1α autophosphorylation activates the RNase activity to cleave XBP1 mRNA, to produce the active transcription factor sXBP1. IRE1α activation also recruits and activates the stress kinase JNK. ATF6α transits to the Golgi compartment where it is cleaved by intramembrane proteolysis to generate a soluble active transcription factor. These UPR pathways act in concert to increase ER content, expand the ER protein folding capacity, degrade misfolded proteins, and reduce the load of new proteins entering the ER. All of these are geared toward adaptation to resolve the protein folding defect. Faced with persistent ER stress, adaptation starts to fail and apoptosis occurs, possibly mediated through calcium perturbations, reactive oxygen species, and the proapoptotic transcription factor CHOP. The UPR is activated in several liver diseases; including obesity associated fatty liver disease, viral hepatitis and alcohol-induced liver injury, all of which are associated with steatosis, raising the possibility that ER stress-dependent alteration in lipid homeostasis is the mechanism that underlies the steatosis. Hepatocyte apoptosis is a pathogenic event in several liver diseases, and may be linked to unresolved ER stress. If this is true, restoration of ER homeostasis prior to ER stress-induced cell death may provide a therapeutic rationale in these diseases. Here we discuss each branch of the UPR and how they may impact hepatocyte function in different pathologic states.
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DOI：
10.1073/pnas.220247197
发表时间：
2000-11-07
影响因子：
11.1
作者：
Brewer, JW;Diehl, JA
通讯作者：
Diehl, JA
影响因子：
16
作者：
Chae, HJ;Kim, HR;Reed, JC
通讯作者：
Reed, JC
影响因子：
5
作者：
Ciccaglione, A. R.;Marcantonio, C.;Rapicetta, M.
通讯作者：
Rapicetta, M.
影响因子：
29
作者：
Back SH;Scheuner D;Han J;Song B;Ribick M;Wang J;Gildersleeve RD;Pennathur S;Kaufman RJ
通讯作者：
Kaufman RJ
影响因子：
4.8
作者：
Chan, SW;Egan, PA
通讯作者：
Egan, PA