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Activation of peroxisome proliferator‐activated receptor‐α inhibits the injurious effects of adiponectin in rat steatotic liver undergoing ischemia–reperfusion
Author(s) -
MassipSalcedo Marta,
Zaouali M. Amine,
PadrissaAltés Susagna,
CasillasRamirez Arani,
Rodés Joan,
RosellóCatafau Joan,
Peralta Carmen
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21935
Subject(s) - adiponectin , endocrinology , medicine , steatosis , peroxisome proliferator activated receptor , peroxisome proliferator activated receptor alpha , oxidative stress , reperfusion injury , biology , chemistry , receptor , ischemia , insulin resistance , transcription factor , nuclear receptor , biochemistry , insulin , gene
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‐α (PPAR‐α), 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‐α and adiponectin in the vulnerability shown by steatotic livers to I/R and the benefits of PC in this situation. PPAR‐α and adiponectin levels in nonsteatotic livers undergoing I/R were similar to those found in the sham group. However, reduced PPAR‐α 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‐α and reduced adiponectin levels in steatotic livers. PC, which increased PPAR‐α, as well as PPAR‐α agonist pretreatment reduced MAPK expression, adiponectin, oxidative stress, and hepatic injury that follows I/R. In addition, the administration of a PPAR‐α 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‐α and overexpress adiponectin when subjected to I/R. PPAR‐α agonists and adiponectin siRNA are promising candidates to protect steatotic livers. PPAR‐α agonists as well as PC, through PPAR‐α, 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. (H EPATOLOGY 2007.)