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Title: Dietary fat source alters hepatic gene expression profile and determines the type of liver pathology in rats overfed via total enteral nutrition

Author
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)
item BAUMGARDNER, JANUARY - University Arkansas For Medical Sciences (UAMS)
item MARECKI, JAY - University Arkansas For Medical Sciences (UAMS)
item HENNINGS, LEAH - University Arkansas For Medical Sciences (UAMS)
item WU, XIANLI - Arkansas Children'S Nutrition Research Center (ACNC)
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)
item CLEVES, MARIO - Arkansas Children'S Nutrition Research Center (ACNC)
item GOMEZ-ACEVEDO, HORATIO - Arkansas Children'S Nutrition Research Center (ACNC)
item Badger, Thomas

Submitted to: Physiological Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/14/2012
Publication Date: 11/15/2012
Citation: Ronis, M.J., Baumgardner, J., Marecki, J., Hennings, L., Wu, X., Shankar, K., Cleves, M., Gomez-Acevedo, H., Badger, T.M. 2012. Dietary fat source alters hepatic gene expression profile and determines the type of liver pathology in rats overfed via total enteral nutrition. Physiological Genomics. 44(22):1073-1089.

Interpretive Summary: Non-alcoholic fatty liver disease (NAFLD) is considered a part of the "metabolic syndrome" associated with obesity and can progress in some patients to cirrhosis, loss of liver function, and liver cancer. NAFLD is now the most common form of liver injury, and rates are rising dramatically as a result of increasing obesity rates. However the biochemical and metabolic mechanisms underlying the development of fatty liver and progression of liver damage to inflammation and fibrosis and the nutritional factors affecting the severity of this disease remain unclear. Part of this is because there are few good animal models that replicate the clinical features of NAFLD and its progression. We have developed a new rat model of NAFLD in which we make the animals obese by overfeeding liquid diets via a stomach tube. This allows us to compare overfeeding diets of different types while keeping the total calories fed the same. In the current study, we used the TEN (total enteral nutrition) model to compare the effects of diets high in carbohydrate or high in three different types of unsaturated fats with different degrees of unsaturation (olive oil, corn oil, and echium oil). After 3 weeks of overfeeding high carbohydrate diets, we observed fat accumulation in liver from rats fed high carbohydrate with olive oil and echium oil but not corn oil. This appeared due to differences in how fatty acids are stored and broken down in the liver of high carbohydrate/corn-oil-fed animals. However, there was no evidence of progression of injury in any group fed high carbohydrates. In contrast, after feeding diets high in olive, corn, and echium oils, all livers were fatty, and liver injury was evident after overfeeding corn oil and echium oil, both of which are polyunsaturated. In contrast, no evidence of cell death was evident after overfeeding olive oil (a monounsaturated fat) even though the livers were full of fat. Liver cell death after corn oil or echium oil was accompanied by an increase in fatty acid breakdown products previously associated with development of liver injury in NAFLD patients clinically. These data suggest that although diets such as the Mediterranean Diet high in monounsaturated fats like olive oil may produce fatty liver, these livers appear to be protected against further injury as a result of the inability of monounsaturated fats compared to polyunsaturated fats to be attacked and broken down by oxygen radicals.

Technical Abstract: This study was designed to determine if the fatty acid composition of the diet affects the development and progression of nonalcoholic fatty liver disease (NAFLD). Male Sprague-Dawley rats (n = 5-6/group) were overfed low (5%) or high (70%) fat diets with different fatty acid sources: olive oil (OO, monounsaturated, mainly 18:1), corn oil (CO, polyunsaturated, mainly 18:2), and echium oil (EO, highly polyunsaturated, mainly 18:3) at 220 kcal/kg3/4/d using total enteral nutrition (TEN) for 21 d. Overfeeding of the 5% CO diet resulted in little steatosis relative to 5% OO and 5% EO (p< 0.05), associated with lower fatty acid synthesis and SREBP-1c signaling (P<0.05), and changes in the mobility of SREBP-1c containing protein complex on the fatty acid synthase promoter in electrophoretic mobility shift assays (EMSA). The 5% and 70% OO groups had macrosteatosis with accumulation of C16:0 and C18:1 triglycerides, but no evidence of oxidative stress or necrosis. The 70% CO and 70% EO groups had a mixture of micro- and macrosteatosis or only microsteatosis, respectively; increased oxidative stress; and increased necrotic injury relative to their respective 5% groups (P<0.05). The extent of oxidative stress and injury correlated with increasing peroxidizability of the accumulated triglycerides. There was no evidence of progression of injury beyond simple steatosis in rats fed MUFA, suggesting a hepato-protective effect relative to PUFAs. These data suggest that: the degree of saturation of dietary fatty acids strongly influences the progression of NAFLD to NASH; and the underlying mechanisms of alcoholic and nonalcoholic steatohepatitis share common features.