Abstract
The pathogenesis of nonalcoholic steatohepatitis (NASH) is a two-stage process in which steatosis is the "first hit" and an unknown "second hit." We hypothesized that "a binge" could be a "second hit" to develop NASH from obesity-induced simple steatosis. Thirty-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) rats were administered 10 mL of 10% ethanol orally for 5, 3, 2, and 1 d/wk for 3 consecutive weeks. As control, male Otsuka Long-Evans Tokushima (OLET) rats were administered the same amount of alcohol. Various biochemical parameters of obesity, steatosis and NASH were monitored in serum and liver specimens in untreated and ethanol-treated rats. The liver sections were evaluated for histopathological alterations of NASH and stained for cytochrome P-4502E1 (CYP2E1) and 4-hydroxy-nonenal (4-HNE). Simple steatosis, hyperinsulinemia, hyperglycemia, insulin resistance, hypertriglycemia and marked increases in hepatic CYP2E1 and 4-HNE were present in 30-wk-old untreated OLETF rats. Massive steatohepatitis with hepatocyte ballooning was observed in the livers of all OLETF rats treated with ethanol. Serum and hepatic triglyceride levels as well as tumor necrosis factor (TNF)-α mRNA were markedly increased in all ethanol-treated OLETF rats. Staining for CYP2E1 and 4-NHE demonstrated marked increases in the hepatic tissue of all the groups of OLETF rats treated with ethanol compared with OLET rats. Our data demonstrated that "a binge" serves as a "second hit" for development of NASH from obesity-induced simple steatosis through aggravation of oxidative stress. The enhanced levels of CYP2E1 and increased oxidative stress in obesity play a significant role in this process.
Highlights
In 1980, Ludwig et al [1] introduced the term “nonalcoholic steatohepatitis” (NASH), and subsequently the more embracing term “nonalcoholic fatty liver disease” (NAFLD) was established to cover the full spectrum of hepatic steatosis associated with insulin resistance and the metabolic syndrome [2]
We observed a significant increase (P < 0.001) in the levels of glucose, insulin, alanine transaminase (ALT) and triglycerides in the serum of 30-wk-old Otsuka Long-Evans Tokushima fatty (OLETF) rats compared with Otsuka Long-Evans Tokushima (OLET) rats, indicating insulin resistance, diabetes, steatosis (Figure 1B, arrow) and increased hepatic uptake of free fatty acids
There was a remarkable increase in the staining intensity of cytochrome P-4502E1 (CYP2E1) on par with aging and increase of body weight in OLETF rats compared with OLET rats
Summary
In 1980, Ludwig et al [1] introduced the term “nonalcoholic steatohepatitis” (NASH), and subsequently the more embracing term “nonalcoholic fatty liver disease” (NAFLD) was established to cover the full spectrum of hepatic steatosis associated with insulin resistance and the metabolic syndrome [2]. The disease does not progress to NASH unless additional molecular events occur (the “second hit”) that result in extensive steatosis, hepatitis, fibrosis and cell death, which are the histological hallmarks of NASH [6]. The “second hit” is generally attributed to oxidative stress that triggers lipid peroxidation of hepatocyte membrane [9]. This process results in production of proinflammatory cytokines and triggers activation of hepatic stellate cells, which initiate liver fibrosis [10,11]. Lipid peroxidation and generation of reactive oxygen species (ROS) can directly and adversely affect hepatocytes, resulting in necrosis and cell death [12]. Increased levels of insulin and fatty acid content have an impact on ROS-mediated cell injury by catalyzing lipid peroxidation either through cy-
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