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Activation of peroxisome proliferator-activated receptor-α inhibits the injurious effects of adiponectin in rat steatotic liver undergoing ischemia–reperfusion

AuthorsMassip-Salcedo, Marta ; Zaouali, Mohamed A. ; Padrissa-Altés, Susagna ; Casillas-Ramírez, Araní ; Rodés, Joan; Roselló-Catafau, Joan ; Peralta, Carmen
Issue Date20-Dec-2007
CitationHepatology 47(2): 461-472 (2008)
AbstractHepatic steatosis is a major risk factor in ischemia–reperfusion (I/R). Adiponectin acts as an antiobesity and anti-inflammatory hormone. Adiponectin activates peroxisome proliferatoractivated receptor- (PPAR- ), 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- and adiponectin in the vulnerability shown by steatotic livers to I/R and the benefits of PC in this situation. PPAR- and adiponectin levels in nonsteatotic livers undergoing I/R were similar to those found in the sham group. However, reduced PPAR- 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- and reduced adiponectin levels in steatotic livers. PC, which increased PPAR- , as well as PPAR- agonist pretreatment reduced MAPK expression, adiponectin, oxidative stress, and hepatic injury that follows I/R. In addition, the administration of a PPAR- antagonist in preconditioned steatotic livers eliminated the beneficial effects of PC on MAPKs, adiponectin, oxidative stress, and hepatic injury. Conclusion: Steatotic livers are more predisposed to down-regulate PPAR- and overexpress adiponectin when subjected to I/R. PPAR- agonists and adiponectin siRNA are promising candidates to protect steatotic livers. PPAR- agonists as well as PC, through PPAR- , 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.
Publisher version (URL)http://dx.doi.org/10.1002/hep.21935
Appears in Collections:(IIBB) Artículos
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