Submitted to: Society of Toxicology
Publication Type: Abstract Only
Publication Acceptance Date: 10/12/2005
Publication Date: 10/20/2005
Citation: Baumgardner, J., Shankar, K., Badger, T.M., Ronis, M.J. 2005. A new rat model for non-alcoholic steatohepatitis [abstract]. In: Proceedings of the South Central Chapter of the Society of Toxicology. 24th Annual Meeting, October 20-21, 2005, Little Rock, Arkansas. p. 18.
Interpretive Summary: The purpose of this study was to develop a model of fatty acid liver disease, know as NASH, in the rat to determine the potential benefits and risks of dietary factors present in human diets on metabolic and endocrine systems. NASH is commonly observed with obesity and diabetes in our aging population and is a complication of childhood obesity. There is no therapy for NASH that has been proven to be clearly effective. Our lack of understanding is largely to due to the lack of a suitable experimental animal model. In this study, we developed an experiment rat model of human NASH; as indicated by increased liver cell death, development of fatty liver, oxidative stress, inflammation and indications of insulin resistance. Using this model, we have demonstrated that increased calories alone are not sufficient to produce fatty liver. However, if the diet contains the same total calories, but the main calorie source is unsaturated fat (like corn oil), NASH develops. Now that we understand something about how NASH develops in this model, we will study the mechanism and determine how to prevent and reverse adverse effects associated with NASH in children.
Technical Abstract: We have developed a new experimental model for non-alcoholic steatohepatitis (NASH) using Total Enteral Nutrition (TEN). We fed male Sprague-Dawley rats (175g) intragastrically by TEN for 21 days. Rats were either fed a standard, 187 kcal/kg3/4/d diet containing 5% corn oil (CO) or a 220 kcal/kg3/4/d diet containing 5, 10, 25, 35, or 70% CO. Rats fed the standard diet had lower body weight gain and significantly less fat as % of body weight (p<0.05) than those fed the increased calorie diet, regardless of the fat content. Oil red O staining showed a dose dependent-increase in triglyceride deposition with increase in % of CO (p<0.05). Pathological examination demonstrated steatosis, macrophage infiltration, and focal necrosis present in the 70% CO group, accompanied by elevated serum ALT levels (p<0.05). An increase in oxidative stress (TBARs) and inflammation, as evidenced by TNF-' mRNA and apoprotein induction (p<0.05), was observed in the 70% CO group. Pathological changes were accompanied by an increase in SREBP-1, a transcription factor associated with fatty acid (FA) biosynthesis, in the 70% CO group (p<0.05). Only slight elevations in PPAR'-dependent CYP4A1 expression (FA '-oxidation), acyl-CoA oxidase mRNA (peroxisomal '-oxidation) and HADHA mRNA (mitochondrial '-oxidation) were observed in the 70% CO group. The data suggest that in this model, FA homeostasis is disrupted, with FA synthesis exceeding FA degradation, leading to steatosis. Hepatic CYP2E1 levels, a source of ROS, increased in rats fed the 70% CO diet (p<0.05) possibly contributing to the observed inflammation. In conclusion, we have successfully developed an experimental model for NASH, as indicated by hepatic pathology, elevated ALT levels, oxidative stress and increased TNF-'. We have demonstrated that increased caloric intake alone is not sufficient to induce steatosis; however, increased caloric intake in the presence of high dietary fat content results in NASH.