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.
Conclusion: 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.