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ORIGINAL RESEARCH COMMUNICATION |
1 From the Section of Liver Disease and Nutrition, Bronx VA Medical Center and Mt Sinai School of Medicine, New York.
Background: Obesity and diabetes are frequently associated with nonalcoholic steatohepatitis (NASH), but studies have been hampered by the absence of a suitable experimental model.
Objective: Our objective was to create a rat model of NASH.
Design: Sprague-Dawley rats were fed a high-fat, liquid diet (71% of energy from fat, 11% from carbohydrates, 18% from protein) or the standard Lieber-DeCarli diet (35% of energy from fat, 47% from carbohydrates, 18% from protein). The diets were given ad libitum or as two-thirds of the amount consumed ad libitum.
Results: Rats fed the high-fat diet ad libitum for 3 wk developed panlobular steatosis, whereas those fed the standard diet had few fat droplets. Accordingly, total lipid concentrations with the high-fat and standard diets were 129.9 ± 9.1 (
± SEM) and 66.7 ± 4.6 mg/g liver, respectively (P < 0.001). The high-fat diet caused abnormal mitochondria and mononuclear inflammation, which were accompanied by increased hepatic tumor necrosis factor 
(TNF-; P < 0.001), TNF- messenger RNA (mRNA) (P < 0.001), collagen type 1, and 1(I) procollagen mRNA (P < 0.001). In addition, these rats had increased cytochrome P4502E1 (CYP2E1) mRNA (P < 0.001), which was accompanied by CYP2E1 induction (P < 0.001) and oxidative stress with increased 4-hydroxynonenal (P < 0.001). Plasma insulin was elevated, which reflected insulin resistance, a NASH pathogenic factor. Rats fed a restricted high-fat diet developed only mild steatosis with attenuated biochemical changes, whereas those given a restricted standard diet had normal livers.
Conclusion: This rat model reproduces the key features of human NASH and provides a realistic experimental model for elucidating its treatment.
Key Words: Model of nonalcoholic steatohepatitis • microsomes • cytochrome P4502E1 • tumor necrosis factor • collagen • 4-hydroxynonenal • insulin resistance • high-fat diet • dietary restriction • oxidative stress • mitochondria
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