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 < or = 0.05), fat mass (P < or = 0.05), and serum
leptin and
glucose levels (P < or = 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 < or = 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 < or = 0.05). An increase in oxidative stress (
thiobarbituric acid-reactive substances) and
TNF-alpha expression (P < or = 0.05) was observed in the 70%
corn oil group, as well as an increase in hepatic
CYP2E1 and CYP4A1 expression (P < or = 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.