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Am J Physiol Gastrointest Liver Physiol (October 18, 2007). doi:10.1152/ajpgi.00296.2007
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Submitted on June 28, 2007
Accepted on October 15, 2007

A New Model For Non-Alcoholic Steatohepatitis in the Rat Utilizing Total Enteral Nutrition to Overfeed a High Polyunsaturated Fat Diet

January Nicole Baumgardner1, Kartik Shankar2, Leah Hennings3, Thomas M. Badger4, and Martin J. J. Ronis1*

1 Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72202, United States; Arkansas Children's Nutrition Center, 1120 Marshall Street, Little Rock, Arkansas, 72202, United States
2 Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72202, United States; Arkansas Children's Nutrition Center, Little Rock, Arkansas, United States
3 Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
4 Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States; Arkansas Children's Nutrition Center, 1120 Marshall Street, Little Rock, Arkansas, 72202, United States

* To whom correspondence should be addressed. E-mail: ronismartinj{at}uams.edu.

We have used total enteral nutrition (TEN) to moderately overfeed rats high polyunsaturated fat diets to develop a model for non-alcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were fed by TEN a 187 kcal/kg3/4/d diet containing 5% (total calories) corn oil or a 220 kcal/kg3/4/d diet in which corn oil constituted 5, 10, 25, 35, 40 or 70% of total calories for 21 or 65 d. Rats fed the 5% corn oil, 220 kcal/kg3/4/d diet had greater body weight gain (p≤0.05), fat mass (p≤0.05), serum leptin and glucose levels (p≤0.05), but no liver pathology. A dose-dependent increase in hepatic triglyceride deposition occurred with increase in % corn oil in the 220 kcal/kg3/4/d groups (p≤0.05). Steatosis, macrophage infiltration, apoptosis and focal necrosis were present in the 70% corn oil group, accompanied by elevated serum ALT levels (p≤0.05). An increase in oxidative stress (TBARS) and TNF{alpha} expression (p≤0.05) was observed in the 70% corn oil group, as well as an increase in hepatic CYP2E1 and CYP4A1 expression (p≤0.05). Significant positive correlations were observed between the level of dietary corn oil and the degree of pathology, ALTs, oxidative stress and inflammation. Liver pathology was progressive with increased necrosis, accompanied by fibrosis, observed after 65 days of TEN. Increased expression of CD36 and L-FABP mRNA suggested development of steatosis was associated with increased fatty acid transport. These data suggest that intragastric infusion of a high polyunsaturated fat diet at a caloric level of 17% excess total calories results in pathology similar to clinical NASH.




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