Chronic liver disease such as cirrhosis, hepatitis, fibrosis, and fatty liver, is associated with reduced levels of S-Adenosylmethionine (AdoMet) in the liver. AdoMct affects a variety of metabolic pathways including methylation, anti-oxidant defense and polyamine production. Evidence from a variety of model systems suggest that dietary supplementation with AdoMet can attenuate liver damage and improve liver function. Despite these intriguing observations, little is known about the effect of AdoMet supplementation at the molecular level. In this R21 exploratory proposal we will examine the effects of AdoMet supplementation at the level of gene expression on a global scale using a rodent model. We will test the hypothesis that hepatotoxins, such as alcohol, have discreet effects on gene expression and that AdoMet supplementation can reverse at least some of these effects. Our experimental approach will use Wistar rats that are assigned to one of six groups: untreated AdoMet treated, alcohol treated, alcohol+AdoMet treated, CCI_ treated, and CC14+AdoMet treated. Using DNA microarrays we will compare global gene expression patterns in each of these groups and determine what! genes and biological pathways are affected by various hepatotoxins and AdoMet supplementation. In addition, we will measure various AdoMet metabolites in the liver to determine the effect of these treatments on AdoMet metabolism. From these studies we will determine how liver hepatotoxins and AdoMet affect gene expression profiles. This information should be informative as to what types of biological pathways are perturbed by these treatments. This knowledge will be useful in understanding the molecular changes that characterized liver disease and the molecular basis for clinical improvement with AdoMet in liver disease. This work may also be useful in the identification of biological pathways affected in chronic liver disease that are not affected by AdoMet supplementation, which may represent other correctable targets in chronic liver disease.
