Model of nonalcoholic steatohepatitis.

Abstract

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 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.

CONCLUSION:

This rat model reproduces the key features of human NASH and provides a realistic experimental model for elucidating its treatment.

• Authors: Charles S Lieber, Maria A Leo, Ki M Mak, Youqing Xu, Qi Cao, Chaoling Ren, Anatoly Ponomarenko, Leonore M DeCarli
• Journal: The American journal of clinical nutrition (Am J Clin Nutr) Vol. 79 Issue 3 Pg. 502-9 (Mar 2004) ISSN: 0002-9165 [Print] United States
• PMID: 14985228 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Collagen Type I
• Dietary Fats
• Insulin
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Cytochrome P-450 CYP2E1

Topics

• Animals
• Collagen Type I (genetics, metabolism)
• Cytochrome P-450 CYP2E1 (genetics, metabolism)
• Diet
• Dietary Fats (administration & dosage)
• Disease Models, Animal
• Eating
• Fatty Liver (etiology, pathology)
• Hepatitis (etiology, pathology)
• Humans
• Insulin (blood)
• Insulin Resistance
• Liver (metabolism, pathology)
• Male
• Oxidative Stress
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Tumor Necrosis Factor-alpha (analysis, genetics)