Institut d′Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
J Pharmacol Exp Ther. 2011 Jul;338(1):143-53. doi: 10.1124/jpet.110.177691. Epub 2011 Apr 12.
Numerous steatotic livers are discarded for transplantation because of their poor tolerance of ischemia-reperfusion (I/R). The injurious effects of retinol-binding protein 4 (RBP4) in various pathologies are well documented. RBP4 levels are reduced by peroxisome proliferator-activated receptor-γ (PPARγ) agonists. Strategies aimed at increasing PPARγ protect steatotic livers under warm ischemia. Ischemic preconditioning (PC) based on brief periods of I/R protects steatotic liver grafts against I/R injury, but the responsible mechanism is poorly understood. We examined the roles of RBP4 and PPARγ in I/R injury associated with steatotic liver transplantation and the benefits of PC in such situations. We report that RBP4 and PPARγ expression levels in nonsteatotic livers were similar to those found in the sham group. However, reduced RBP4 and increased PPARγ levels were observed in steatotic livers. Treatment with either RBP4 or a PPARγ antagonist was effective only in steatotic livers. PC, which increased RBP4 levels, and RBP4 treatment both reduced PPARγ levels and hepatic injury in steatotic livers. When PPARγ was activated, neither RBP4 treatment nor PC (despite RBP4 induction) protected steatotic livers. In conclusion, steatotic liver grafts are more predisposed to down-regulate RBP4 and overexpress PPARγ. RBP4 treatment and PC, through RBP4 induction, reduced PPARγ levels in steatotic liver grafts, thus protecting them from the PPARγ detrimental effects.
许多脂肪肝因不耐受缺血再灌注（I/R）而被丢弃用于移植。视黄醇结合蛋白 4（RBP4）在各种病理中的损伤作用已有充分记录。过氧化物酶体增殖物激活受体-γ（PPARγ）激动剂可降低 RBP4 水平。旨在增加 PPARγ 的策略可在暖缺血期间保护脂肪肝。基于短暂 I/R 的缺血预处理（PC）可保护脂肪肝移植物免受 I/R 损伤，但负责的机制知之甚少。我们研究了 RBP4 和 PPARγ 在与脂肪肝移植相关的 I/R 损伤中的作用，以及 PC 在这种情况下的益处。我们报告说，非脂肪肝中的 RBP4 和 PPARγ 表达水平与假手术组相似。然而，在脂肪肝中观察到 RBP4 减少和 PPARγ 水平增加。RBP4 或 PPARγ 拮抗剂的治疗仅在脂肪肝中有效。增加 RBP4 水平的 PC 以及 RBP4 治疗均降低了脂肪肝中的 PPARγ 水平并减轻了肝损伤。当激活 PPARγ 时，RBP4 治疗或 PC（尽管 RBP4 诱导）均不能保护脂肪肝。总之，脂肪肝移植物更容易下调 RBP4 并过表达 PPARγ。RBP4 治疗和 PC 通过 RBP4 诱导降低了脂肪肝中 PPARγ 水平，从而保护它们免受 PPARγ 的有害影响。
