The contribution of endoplasmic reticulum stress to liver diseases.
The contribution of endoplasmic reticulum stress to liver diseases.
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DOI：
10.1002/hep.24279
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发表时间：
2011-05
期刊：
影响因子：
13.5
通讯作者：
Kaplowitz, Neil
中科院分区：
文献类型：
--
作者：
Dara, Lily;Ji, Cheng;Kaplowitz, Neil
未折叠蛋白应答(UPR)是一种进化上保守的细胞信号通路，当细胞受到客户蛋白负荷增加或未折叠或错误折叠蛋白积累的压力时，它被激活以调节蛋白质的合成并恢复动态平衡。一旦被激活，这个信号通路可以导致内稳态的恢复，也可以激活一系列事件，最终导致细胞死亡。UPR/ER应激反应谱及其与其他细胞器的相互作用在富含内质网的分泌细胞(如肝细胞)的疾病发病机制中起着重要作用。在过去的二十年里，人们研究了内质网应激对各种形式的肝病的贡献。在非酒精性脂肪性肝炎(NASH)、酒精性肝病、缺血再灌注损伤和肝病的胆汁淤积模型中，强烈支持内质网应激反应起作用而不是辅助作用。细胞损伤模式和内质网应激之间的因果关系的确切方向仍然难以捉摸。很明显，内质网应激反应、促进内质网应激的条件以及由此产生的条件之间存在着复杂的相互作用。内质网应激促进炎症、细胞损伤和脂肪变性的恶性循环，以及脂肪生成、炎症和细胞损伤加重内质网应激似乎正在发挥作用。也许正是这种恶性循环的本质，才是关键的病理生理学概念。旨在中断循环的治疗方法可能会抑制应激反应和随后的伤害。
The unfolded protein response (UPR) is an evolutionarily conserved cell signaling pathway which is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed from increased client protein load or the accumulation of unfolded or malfolded proteins. Once activated, this signaling pathway can either result in the recovery of homeostasis, , or can activate a cascade of events which ultimately result in cell death. The UPR/ER stress response spectrum and its interplay with other cellular organelles play an important role in the pathogenesis of disease in secretory cells rich in endoplasmic reticulum, such as hepatocytes. Over the past two decades the contribution of ER stress to various forms of liver diseases has been examined. Robust support for a contributing as opposed to a secondary role for ER stress response is seen in the nonalcoholic steatohepatitis (NASH), alcoholic liver disease, ischemia reperfusion injury and cholestatic models of liver disease. The exact direction of the cause and effect relationship between modes of cell injury and ER stress remains elusive. It is apparent that a complex interplay exists between ER stress response, conditions that promote it, and those that result from it. A vicious cycle in which ER stress promotes inflammation, cell injury and steatosis and in which steatogenesis, inflammation and cell injury aggravate ER stress seems to be at play. It is perhaps the nature of such a vicious cycle that is the key pathophysiologic concept. Therapeutic approaches aimed at interrupting the cycle may dampen the stress response and the ensuing injury.
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