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1 Division of Gastrointestinal and Liver Diseases, University of Southern California-University of California, Los Angeles, Research Center for Alcoholic Liver and Pancreatic Diseases and University of Southern California Research Center for Liver Disease, University of Southern California School of Medicine, Los Angeles, California 90033; and 2 Division of Hepatology and Gene Therapy, University of Navarra School of Medicine, 31008 Pamplona, Spain
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 expression was associated with more rapid cell growth. Changes in MAT expression have not been examined in animal models of alcoholic liver injury, which 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 doubled but only the protein level of MAT2A increased. Although liver-specific MAT activity did not change, it was 32% lower after one and 68% lower after eight weekly enteral doses of lipopolysaccharide. Hepatic levels of methionine, SAM, and DNA methylation fell by ~40%. c-myc was hypomethylated, and its mRNA level increased. Genome-wide DNA strand break increased. Thus in the prefibrotic stage of alcoholic liver injury, there is already a switch in MAT expression, global DNA hypomethylation, increased c-myc expression, and genome-wide DNA strand break. These changes may be important in predisposing this liver disease to malignant degeneration.
deoxyribonucleic acid methylation; c-myc; deoxyribonucleic acid stability; methionine metabolism; liver cancer
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