Mechanisms of ischemic injury are different in the steatotic and normal rat liver

Hepatic steatosis is associated with significant morbidity and mortality af ter liver resection and transplantation. Although apoptosis is a key mechan ism of reperfusion injury in the normal liver, the pathway leading to cell death in steatotic hepatocytes is unknown. A model of hepatic ischemia and reperfusion injury in fatty and lean Zucker rats was used. Fatty animals ha d increased aspartate aminotransferase (AST) release and decreased survival after 60 minutes of ischemia compared with lean animals. Apoptosis was the predominant form of cell death in the lean rats (82%), whereas necrosis wa s minimal. In contrast, fatty animals developed only moderate amounts of ap optosis but showed massive necrosis (73%) after 24 hours of reperfusion. In tracellular mediators of apoptosis, such as caspase 8, caspase 3, and cytoc hrome c, were significantly lower in the steatotic than in the lean liver i ndicating dysfunction in activation of the apoptotic pathway. The high perc entage of necrosis in the steatotic rats was associated with renal acute tu bular necrosis after 24 hours of reperfusion in the fatty, but not in lean rats. Caspase inhibition significantly decreased reperfusion injury in lean animals, but was ineffective in fatty animals. The results indicate that t he increased susceptibility of fatty livers to reperfusion injury is associ ated with a change from an apoptotic form of cell death to necrosis. We con clude that new therapeutic strategies are necessary in the fatty liver.