Model of nonalcoholic steatohepatitis.
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.


METHODS
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 alpha (TNF-alpha; P < 0.001), TNF-alpha messenger RNA (mRNA) (P < 0.001), collagen type 1, and alpha1(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.


CONCLUSIONS
This rat model reproduces the key features of human NASH and provides a realistic experimental model for elucidating its treatment.
Section of Liver Disease and Nutrition, Bronx VA Medical Center and Mt Sinai School of Medicine, New York 10468, USA. liebercs@aol.com
Charles S
CS
Lieber
Maria A
MA
Leo
Ki M
KM
Mak
Youqing
Y
Xu
Qi
Q
Cao
Chaoling
C
Ren
Anatoly
A
Ponomarenko
Leonore M
LM
DeCarli
D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004435:Eating; D005234:Fatty Liver / Q000209:etiology / Q000473:pathology; D006505:Hepatitis / Q000209:etiology / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics
D024042:Collagen Type I; D004041:Dietary Fats; D007328:Insulin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019392:Cytochrome P-450 CYP2E1