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

Abstract

Hepatic steatosis is associated with significant morbidity and mortality after liver resection and transplantation. Although apoptosis is a key mechanism 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 had 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 was minimal. In contrast, fatty animals developed only moderate amounts of apoptosis but showed massive necrosis (73%) after 24 hours of reperfusion. Intracellular mediators of apoptosis, such as caspase 8, caspase 3, and cytochrome c, were significantly lower in the steatotic than in the lean liver indicating dysfunction in activation of the apoptotic pathway. The high percentage of necrosis in the steatotic rats was associated with renal acute tubular 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 the increased susceptibility of fatty livers to reperfusion injury is associated with a change from an apoptotic form of cell death to necrosis. We conclude that new therapeutic strategies are necessary in the fatty liver.

Visceral adiposity and insulin resistance are independent predictors of the presence of non-cirrhotic NAFLD-related portal hypertension

“…3,4 This increased vulnerability might be explained by the impact of steatosis on mechanisms of inflammation, fibrogenesis and regeneration. [5][6][7] However, changes in liver blood flow, especially a reduction in sinusoidal flow, 8,9 were documented as well, both in animals 9 and in humans. 8 We recently demonstrated in the methionine-cholinedeficient diet-induced rat model of steatosis that steatosis induces significant portal hypertension (PHT) in the absence of fibrosis and morphological signs of inflammation.…”

Ischemia-Reperfusion Injury Associated with Liver Transplantation in 2011: Past and Future

“…2). , 2010;Casillas et al, 2006;Fernández et al, 2004;Ghobrial et al, 2005;Jaeschke &Lemasters, 2003;Malhi et al, 2006;Massip-Salcedo et al, 2007;Selzner et al, 2000;Yin, 2000) …”

“…Hepatocyte damage appears remarkably higher in steatotic livers than in non-steatotic livers Selzner et al, 2000). Several evidences indicate that an increased sensitivity of fatty hepatocytes to the injurious effects of ROS could explain the poor tolerance of steatotic livers to I/R (Koneru et al, 2005;Soltys et al, 2001).…”

“…Operative mortality associated with steatosis exceeds 14%, compared with 2% for healthy livers, and the risks of primary non-function and dysfunction after surgery are similarly higher Selzner et al, 2000). Thus, hepatic steatosis is the major cause of graft rejection after LT and exacerbates the organ shortage problem (Fernández et al, 2004).…”

Noninvasive estimation of hepatic steatosis using plain CT vs. Chemical‐shift MR imaging: Significance for living donors

“…Also, in living donor liver transplantation (LDLT), the extent of hepatic steatosis in the living donor could influence recipient outcome as well as potentially affect recovery of the donor after partial hepatectomy (5,6). In the previous studies, it has been showed that body mass index (BMI) is a predictor of the presence but not of the extent of hepatic steatosis (7).…”