Changes in methionine adenosyltransferase and S-adenosylmethionine homeostasis in alcoholic rat liver

Liver-specific and non-liver-specific methionine adenosyltransferase (MAT) are products of two genes, MAT1A and MAT2A, respectively, that catalyze the formation of S-adenosylmethionine (SAM). We previously showed that MAT2A e xpression was associated with more rapid cell growth. Changes in MAT expres sion have not been examined in animal models of alcoholic liver injury, whi ch is the focus of the current study. After rats were fed intragastrically with ethanol and high fat for 9 wk, the mRNA level of both MAT forms double d but only the protein level of MAT2A increased. Although liver-specific MA T activity did not change, it was 32% lower after one and 68% lower after e ight weekly enteral doses of lipopolysaccharide. Hepatic levels of methioni ne, SAM, and DNA methylation fell by similar to 40%. c-myc was hypomethylat ed, and its mRNA level increased. Genome-wide DNA strand break increased. T hus in the prefibrotic stage of alcoholic liver injury, there is already a switch in MAT expression, global DNA hypomethylation, increased c-myc expre ssion, and genome-wide DNA strand break. These changes may be important in predisposing this liver disease to malignant degeneration.