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Am J Physiol Gastrointest Liver Physiol 294: G27-G38, 2008. First published October 18, 2007; doi:10.1152/ajpgi.00296.2007
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LIVER AND BILIARY TRACT

A new model for nonalcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a high-polyunsaturated fat diet

January N. Baumgardner,1,4 Kartik Shankar,1,4 Leah Hennings,3 Thomas M. Badger,1,2,4 and Martin J. J. Ronis1,4

1Departments of Pharmacology and Toxicology, 2Physiology and Biophysics and 3Pathology, University of Arkansas for Medical Sciences; and 4Arkansas Children's Nutrition Center, Little Rock, Arkansas

Submitted 28 June 2007 ; accepted in final form 15 October 2007

We have used total enteral nutrition (TEN) to moderately overfeed rats high-polyunsaturated fat diets to develop a model for nonalcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were fed by TEN a 187 kcal·kg–3/4·day–1 diet containing 5% (total calories) corn oil or a 220 kcal·kg–3/4·day–1 diet in which corn oil constituted 5, 10, 25, 35, 40, or 70% of total calories for 21 or 65 days. Rats fed the 5% corn oil, 220 kcal·kg–3/4·day–1 diet had greater body weight gain (P ≤ 0.05), fat mass (P ≤ 0.05), and serum leptin and glucose levels (P ≤ 0.05), but no liver pathology. A dose-dependent increase in hepatic triglyceride deposition occurred with increase in percent corn oil in the 220 kcal·kg–3/4·day–1 groups (P ≤ 0.05). Steatosis, macrophage infiltration, apoptosis, and focal necrosis were present in the 70% corn oil group, accompanied by elevated serum alanine aminotransferase (ALT) levels (P ≤ 0.05). An increase in oxidative stress (thiobarbituric acid-reactive substances) 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.

obesity; oxidative stress; tumor necrosis factor-alpha, CD36; liver fatty acid binding protein


Address for reprint requests and other correspondence: M. J. J. Ronis, Arkansas Children's Nutrition Center, Slot 512-20B, 1212 Marshall St., Little Rock, AR 72202 (e-mail: RonisMartinJ{at}uams.edu)




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