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.
Wang
Yan
Y
Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
Ausman
Lynne M
LM
Russell
Robert M
RM
Greenberg
Andrew S
AS
Wang
Xiang-Dong
XD
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001835:Body Weight; D004041:Dietary Fats / Q000009:adverse effects*; D004789:Enzyme Activation; D005234:Fatty Liver / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015227:Lipid Peroxidation; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D008297:Male; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D004041:Dietary Fats; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases