Increased apoptosis in high-fat diet-induced nonalcoholic steatohepatitis in rats is associated with c-Jun NH2-terminal kinase activation and elevated proapoptotic Bax

Hepatocyte apoptosis in addition to oxidative stress could be a key component in the pathogenesis of nonalcoholic steatohepatitis {(NASH).} However, the underlying mechanisms of hepatocellular apoptotic response associated with oxidative stress have not been investigated in high-fat diet {(HFD)-induced} {NASH} models. In this study, {Sprague-Dawley} rats were fed either a {Lieber-DeCarli} control diet {(CD;} 35% energy from fat) or a {HFD} (71% energy from fat) for 6 wk. Pathologic lesions, lipid peroxidation products, and apoptotic hepatocytes in the liver were examined. The expressions of hepatic tumor necrosis factor-alpha {(TNFalpha)} and protein concentrations of cleaved caspase-3, cytochrome {p4502E1} {(CYP2E1),} phosphorylated {c-Jun} {NH(2)-terminal} kinase {(JNK),} Bax, Bcl-2, and Bcl-xl were measured. Results showed that the key histological features of {NASH,} including steatosis, inflammatory cell infiltration, and ballooning degeneration of hepatocytes, were induced by {HFD} feeding, with increased hepatic {TNFalpha} {mRNA} expression. {HFD-fed} rats had elevated lipid peroxidation products and {CYP2E1} protein in the liver. The apoptotic hepatocytes were significantly greater in livers of rats fed {HFD} than in those fed {CD,} and these were associated with a higher level of cleaved caspase-3. In addition, {HFD} feeding increased both hepatic phosphorylated {JNK} and pro-apoptotic Bax but did not affect anti-apoptotic Bcl-2 and Bcl-xl compared with {CD} feeding. These data indicate that the increased oxidative stress and its associated {JNK} activation as well as an imbalance of pro- and anti-apoptotic proteins in the Bcl-2 family all contribute to high hepatocyte apoptosis that may play an important role in the pathogenesis of {NASH} in this model.