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

Author
item BAUMGARDNER, JANUARY
item SHANKAR, KARTIK
item HENNINGS, LEAH
item BADGER, THOMAS
item RONIS, MARTIN

Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/15/2007
Publication Date: 1/15/2008
Citation: Baumgardner, J.N., Shankar, K., Hennings, L., Badger, T.M., Ronis, M.J. 2008. A new model for non-alcoholic steatohepatitis in the rat utilizing total enteral nutrition to overfeed a high polyunsaturated fat diet. American Journal of Physiology - Gastrointestinal and Liver Physiology. 294(2):G27-G38.

Interpretive Summary: With obesity becoming the number one health issue facing the United States, there is a need to have animal models that allow in-depth research into the cause of diseases and disorders associated with obesity and overweight. NASH, or non-alcoholic steatohepatitis, is a disease of the liver associated with a large percentage of obese subjects. Although characterizing the NASH liver is straightforward, understanding how it got into the diseased condition may be important in such things as: being able to predict who will get NASH, preventing NASH, and treating NASH. Until our report, there were no good animal models to study this condition. We have developed a rat model that has most of the important biochemical and physiological features of NASH ,and we plan to use this model to learn more about the disease and to develop treatment and prevention strategies.

Technical Abstract: 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/kg 3/4 /d diet containing 5% (total calories) corn oil or a 220 kcal/kg 3/4 /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 (p0.05), fat mass (p0.05), serum leptin, and glucose levels (p0.05), 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 /d groups (p0.05). Steatosis, macrophage infiltration, apoptosis, and focal necrosis were present in the 70% corn oil group, accompanied by elevated serum ALT levels (p0.05). An increase in oxidative stress (TBARS) and TNF expression (p0.05) was observed in the 70% corn oil group, as well as an increase in hepatic CYP2E1 and CYP4A1 expression (p0.05). 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.