Massip-Salcedo Marta, Zaouali M Amine, Padrissa-Altés Susagna, Casillas-Ramirez Arani, Rodés Joan, Roselló-Catafau Joan, Peralta Carmen
Experimental Hepatic Ischemia-Reperfusion Unit, IIBB-CSIC Barcelona, Spain.
Hepatology. 2008 Feb;47(2):461-72. doi: 10.1002/hep.21935.
Hepatic steatosis is a major risk factor in ischemia-reperfusion (I/R). Adiponectin acts as an antiobesity and anti-inflammatory hormone. Adiponectin activates peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a transcription factor that regulates inflammation in liver disease. Ischemic preconditioning (PC) based on brief periods of I/R protects steatotic livers against subsequent sustained I/R injury, but just how this is achieved is poorly understood. This study explains the role of PPAR-alpha and adiponectin in the vulnerability shown by steatotic livers to I/R and the benefits of PC in this situation. PPAR-alpha and adiponectin levels in nonsteatotic livers undergoing I/R were similar to those found in the sham group. However, reduced PPAR-alpha and increased adiponectin levels, particularly the high molecular weight isoform, were observed in steatotic livers as a consequence of I/R. Our results suggest that mitogen-activated protein kinases (MAPKs) may be positive regulators of adiponectin accumulation in steatotic livers. The addition of adiponectin small interfering RNA (siRNA) before I/R protected steatotic livers against oxidative stress and hepatic injury. The induction of PC before I/R increased PPAR-alpha and reduced adiponectin levels in steatotic livers. PC, which increased PPAR-alpha, as well as PPAR-alpha agonist pretreatment reduced MAPK expression, adiponectin, oxidative stress, and hepatic injury that follows I/R. In addition, the administration of a PPAR-alpha antagonist in preconditioned steatotic livers eliminated the beneficial effects of PC on MAPKs, adiponectin, oxidative stress, and hepatic injury.
Steatotic livers are more predisposed to down-regulate PPAR-alpha and overexpress adiponectin when subjected to I/R. PPAR-alpha agonists and adiponectin siRNA are promising candidates to protect steatotic livers. PPAR-alpha agonists as well as PC, through PPAR-alpha, inhibited MAPK expression following I/R. This in turn inhibited adiponectin accumulation in steatotic livers and adiponectin-worsening effects on oxidative stress and hepatic injury.
肝脂肪变性是缺血再灌注（I/R）的主要危险因素。脂联素作为一种抗肥胖和抗炎激素。脂联素激活过氧化物酶体增殖物激活受体α（PPAR-α），这是一种调节肝病炎症的转录因子。基于短暂I/R的缺血预处理（PC）可保护脂肪变性肝脏免受随后的持续性I/R损伤，但目前对其具体实现方式了解甚少。本研究解释了PPAR-α和脂联素在脂肪变性肝脏对I/R的易感性中所起的作用以及PC在这种情况下的益处。接受I/R的非脂肪变性肝脏中的PPAR-α和脂联素水平与假手术组相似。然而，由于I/R，在脂肪变性肝脏中观察到PPAR-α水平降低且脂联素水平升高，尤其是高分子量异构体。我们的结果表明，丝裂原活化蛋白激酶（MAPK）可能是脂肪变性肝脏中脂联素积累的正调节因子。在I/R前添加脂联素小干扰RNA（siRNA）可保护脂肪变性肝脏免受氧化应激和肝损伤。I/R前诱导PC可增加脂肪变性肝脏中的PPAR-α并降低脂联素水平。增加PPAR-α的PC以及PPAR-α激动剂预处理可降低MAPK表达、脂联素、氧化应激以及I/R后的肝损伤。此外，在预处理的脂肪变性肝脏中给予PPAR-α拮抗剂可消除PC对MAPK、脂联素、氧化应激和肝损伤的有益作用。
脂肪变性肝脏在接受I/R时更易下调PPAR-α并过度表达脂联素。PPAR-α激动剂和脂联素siRNA是保护脂肪变性肝脏的有前景的候选药物。PPAR-α激动剂以及PC通过PPAR-α抑制I/R后的MAPK表达。这反过来又抑制了脂肪变性肝脏中脂联素的积累以及脂联素对氧化应激和肝损伤的恶化作用。
