Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/26/2008
Publication Date: 10/3/2008
Citation: Baumgardner, J.N., Shankar, K., Hennings, L., Albano, E., Badger, T.M., Ronis, M.J. 2008. N-acetylcysteine attenuates progression of liver pathology in a rat model of nonalcoholic steatohepatitis. Journal of Nutrition. 138(10):1872-1879.
Interpretive Summary: Non-alcoholic steatohepatitis (NASH) is a common complication of childhood and adult obesity. It is associated with accumulation of fat in the liver and can progress to inflammation, cellular injury, and fibrosis, ultimately resulting in reduced liver function. There is no therapy for NASH that has been proven to be clearly effective, but there is data to suggest that oxidative stress is a key feature in progression of the disease from simple fatty liver to hepatitis and fibrosis. We have successfully developed a new rat model to study NASH. The rats are essentially overfed a high unsaturated fat diet using liquid diets fed directly into the stomach via a tube (total enteral nutrition), the same procedures used clinically to feed ill children in the hospital. In addition, using this model, we have found endocrine, biochemical, and molecular changes similar to NASH patients, accompanied by changes in liver pathology, including fat accumulation, inflammation, and fibrosis. In this study we found that N-acetylcysteine (NAC), an antioxidant commonly used as a food preservative, may be an effective treatment for NASH. We observed that adding NAC to the diet abolished oxidative stress, prevented progression from fatty liver to hepatitis and fibrosis, and reduced evidence of inflammation and auto-immune responses to oxidized proteins. These are important findings, and this model will be used in future studies to learn more about how to prevent and treat this complication associated with obesity.
Technical Abstract: A "two-hit" model for non-alcoholic steatohepatitis (NASH) has been proposed in which steatosis constitutes the "first hit" and sensitizes the liver to potential "second hits" resulting in NASH. Oxidative stress is considered a candidate for the second hit. N-acetylcysteine (NAC), an antioxidant, has been suggested as a dietary therapy for NASH. We examined effects of NAC in a rat total enteral nutrition (TEN) model where NASH develops as the result of overfeeding dietary polyunsaturated fat. Male Sprague-Dawley rats were fed pelleted AIN-93G diets ad libitum or were overfed a 220 kcal/kg 3/4/d liquid diet containing 70% corn oil with or without 2 g/kg/d NAC intragastrically for 65 d. Hepatic steatosis was not influenced by dietary supplementation with NAC; however, the liver pathology score was significantly lower (p greater than or equal to 0.05). NAC attenuated increased hepatic oxidative stress (TBARS: (p less than or equal to 0.05); prevented increases in CYP2E1 apoprotein and mRNA; and TNF-alpha mRNA. A decrease in titers of auto-antibodies against proteins adducted to lipid peroxidation products was observed in the NAC group relative to the 70% corn oil group (p less than or equal to 0.05). NAC also decreased Picosirius red staining of collagen, a marker of fibrosis. However, markers of hepatic stellate cell activiation (TGF-beta, alpha-AMA, and PDGFr-beta mRNA) were unaffected. Using NAC in a TEN model for NASH we have demonstrated that NAC prevents many aspects of NASH progression by decreasing development of oxidative stress and subsequent increases in TNF-alpha, but is unable to block development of steatosis.