Nutritional status and diet are important variables that influence cellular responses to toxins. This is particularly true in experimental models of alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH). Although their primary etiology is different, these diseases show almost identical histology. To investigate the role of nutrition in ASH and NASH, I have used an intragastric infusion model in which diet and ethanol dosing can be completely controlled. I investigated the effects of reduced caloric intake on the early stages of alcohol-induced liver disease (ALD), specifically ASH, using Total Enteral Nutrition (TEN). I found that undernutrition does not exacerbate ALD, but appears to provide a protective response to enhanced oxidative stress. Because the histopathological abnormalities in NASH mimic those of ASH, I have used the same TEN system to develop an experimental rat model for NASH. In this model, I produced NASH by altering the amount and type of dietary fat (without alcohol) in the diet. I found that overfeeding diets rich in polyunsaturated fats increased the severity of NASH. Oxidative stress is thought to play a significant role in the progression of NASH; therefore, I examined the effects of N-acetylcysteine (NAC), an antioxidant, in the NASH model. I have demonstrated that NAC prevents many aspects of NASH progression, but is unable to block development of steatosis. My studies demonstrate that oxidative stress is a common underlying mechanism of hepatocellular damage in both ASH and NASH; however, the major stimulant of free radical production (ethanol + polyunsaturated fats or polyunsaturated fats alone) and the molecular mechanisms underlying the development of steatosis differ. My data suggests that undernutrition is protective in ALD by favoring repair pathways even though oxidative stress is increased, while overnutrition results in increased pathology, perhaps via insulin resistance, altered adipokines and increased non-esterified fatty acid production direct lipotoxicity. Considering that NASH shows a close correlation with obesity and/or insulin resistance and that insulin resistance indirectly leads to oxidative stress via excessive fatty acids in the hepatocytes, the difference in the nutritional status between ASH and NASH may closely associate with the mechanisms of hepatocellular damage in these diseases.Nutritional status and diet are important variables that influence cellular responses to toxins. This is particularly true in experimental models of alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH).
|Title||:||Effects of Diet and Nutritional Status on Progression of Fatty Liver Disease in Rats Fed Via Total Enteral Nutrition|
|Author||:||January N. Baumgardner|
|Publisher||:||ProQuest - 2007|