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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #254887
Title: Effects of long term ethanol administration in a rat total enteral nutrition model of alcoholic liver disease

Author
item RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)
item HENNINGS, LEAH - University Arkansas For Medical Sciences (UAMS)
item STEWART, BEN - University Of Colorado
item BASNAKIAN, ALEXEI - University Arkansas For Medical Sciences (UAMS)
item APOSTALOV, EUGENE - University Arkansas For Medical Sciences (UAMS)
item ALBANO, EMANUELE - University Of Colorado
item Badger, Thomas
item PETERSEN, DENNIS - University Of Colorado

Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/29/2010
Publication Date: 1/12/2011
Citation: Ronis, M.J., Hennings, L., Stewart, B., Basnakian, A.G., Apostalov, E.O., Albano, E., Badger, T.M., Petersen, D.R. 2011. Effects of long term ethanol administration in a rat total enteral nutrition model of alcoholic liver disease. American Journal of Physiology - Gastrointestinal and Liver Physiology. 300(1):G109-G119.

Interpretive Summary: Despite many years of research, the molecular mechanisms underlying progression of alcoholic liver injury from simple fatty liver through hepatitis to fibrosis and cirrhosis remain in dispute. In the current study male Sprague-Dawley rats (350 g) were chronically fed a high unsaturated fat diet for 120 d using a feeding tube, or a diet in which ethanol (EtOH) replaced carbohydrate calories. Additional control and EtOH-treated groups were supplemented with the antioxidant N-acetylcysteine (NAC) at 1.7 g/kg/d. Relative to a chow-fed group, long term feeding of the high fat diets resulted in development of mild fatty liver, but no other liver injury. Supplementation with NAC resulted in increased overall growth rates and marked appearance of liver fat, but no other evidence of liver injury. EtOH produced fatty liver, inflammation and cell death and the appearance of fibrosis as determined by staining for collagen. This was accompanied by increases in expression of genes coding for collagen. Surprisingly, although the combination of EtOH and NAC prevented EtOH-associated oxidative stress and cellular injury apparently as the result of increased cell division of pre-existing liver cells (hepatocytes) rather than as a result of differentiation of resident stem cells into new liver cells, fat infiltration of liver was elevated over NAC or EtOH treatment alone, and collagen staining was unchanged or even increased relative

Technical Abstract: Male Sprague-Dawley rats were chronically fed a high unsaturated fat diet for 130 d using total enteral nutrition (TEN), or the same diet in which ethanol (EtOH) isocalorically replaced carbohydrate calories. Additional control and EtOH-treated groups were supplemented with the antioxidant N-acetylcysteine (NAC) at 1.7 g/kg/d. Relative to an ad libitum chow-fed group, the high fat group developed mild steatosis, but little other hepatic pathology. NAC by itself resulted in increased somatic growth (P<0.05) and marked increases in hepatic steatosis (P<0.05), without elevation in serum ALT. Chronic EtOH produced marked hepatic steatosis and oxidative stress. In spite of a 2-fold elevation in serum ALT, no changes in tumor necrosis factor'alpha or tumor growth factor'beta expression were observed. Fibrosis was evident based on Masson-Trichrome and Picosirius Red staining and a 2-fold increase in expression of Type I and Type III collagen mRNA (P< 0.05). Long term alcohol treatment did not modify the hepatic mRNAs for hedgehog pathway ligands or target genes or genes regulating epithelial-to-mesenchymal transition (EMT). Although NAC prevented oxidative stress and necrosis; and had additive effects on hepatocyte proliferation, hepatic steatosis was unaffected and effects on fibrosis were negligible. These data suggest that the TEN model can be utilized to study additional mechanisms unrelated to inflammation or oxidative stress which contribute to the progression of alcoholic liver damage toward fibrosis.