Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
Clin Sci (Lond). 2012 Jul;123(2):93-8. doi: 10.1042/CS20110093.
In the present Hypothesis article, we summarize and present data from the literature that support our hypothesis on the potential mechanisms by which UPS (ubiquitin-proteasome system) inhibitors reduce I/R (ischaemia/reperfusion) injury in the liver. I/R is the main cause of primary liver failure and, consequently, minimizing the detrimental effects of this process could increase the number of suitable transplantation grafts and also enhance the survival rate of patients after liver transplantation. A potential strategy to reduce I/R injury is the use of UPS inhibitors either as additives to preservation solutions or as drugs administered to patients. However, there is still controversy over whether the use of UPS inhibitors is beneficial or deleterious with regard to liver injury. From our experience and the few studies that have investigated the role of UPS in hepatic I/R, we believe that the use of UPS inhibitors is a potential strategy to reduce I/R injury in liver transplantation and graft preservation. We hypothesize that one of the main mechanisms of action of UPS inhibitors may be the up-regulation of AMPK (AMP-activated protein kinase) activity and the consequent down-regulation of mTOR (mammalian target of rapamycin), which may finally influence autophagy and preserve the energy state of the cell.
在本假说文章中，我们总结并呈现了来自文献的数据，这些数据支持我们关于 UPS（泛素-蛋白酶体系统）抑制剂降低肝脏 I/R（缺血/再灌注）损伤的潜在机制的假说。I/R 是原发性肝衰竭的主要原因，因此，最大限度地减少这一过程的有害影响可以增加合适的移植供体数量，并提高肝移植后患者的生存率。减少 I/R 损伤的一种潜在策略是使用 UPS 抑制剂作为保存液的添加剂或作为给予患者的药物。然而，关于 UPS 抑制剂在肝损伤方面的使用是否有益还是有害，仍存在争议。根据我们的经验和少数研究 UPS 在肝 I/R 中的作用，我们认为使用 UPS 抑制剂是减少肝移植和供体保存中 I/R 损伤的一种潜在策略。我们假设 UPS 抑制剂的主要作用机制之一可能是上调 AMPK（AMP 激活的蛋白激酶）活性，从而下调 mTOR（雷帕霉素的哺乳动物靶标），这最终可能影响自噬并维持细胞的能量状态。
