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Of the two genes that encode methionine adenosyltransferase(MAT1A and MAT2A), MAT1A is mainly expressed in adult liver whereas MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic S\u2010adenosylmethionine content and hyperplasia and spontaneously develop nonalcoholic steatohepatitis. In this study, we examined whether chronic hepatic Sadenosylmethionine deficiency generates oxidative stress and predisposes to injury and malignant transformation. Differential gene expression in MAT1A knockout mice was analyzed following the criteria of the Gene Ontology Consortium. Susceptibility of MAT1A knockout mice to CCl4\u2010induced hepatotoxicity and malignant transformation was determined in 3\u2010 and 18month\u2010old mice, respectively. Analysis of gene expression profiles revealed an abnormal expression of genes involved in the metabolism of lipids and carbohydrates in MAT1A knockout mice, a situation that is reminiscent of that found in diabetes, obesity, and other conditions associated with nonalcoholic steatohepatitis. This aberrant expression of metabolic genes in the knockout mice was associated with hyperglycemia, increased hepatic CYP2E1 and UCP2 expression and triglyceride levels, and reduced hepatic glutathione content. The knockout animals have increased lipid peroxidation and enhanced sensitivity to CCl4\u2010induced liver damage, which was largely due to increased CYP2E1 expression because diallyl sulfide, an inhibitor of CYP2E1, prevented CCl4\u2010induced liver injury. Hepatocellular carcinoma developed in more than half of the knockout mice by 18 months of age. Taken together, our findings define a critical role for S\u2010adenosylmethionine in maintaining normal hepatic function and tumorigenesis of the liver.<\/jats:p>","DOI":"10.1096\/fj.02-0078fje","type":"journal-article","created":{"date-parts":[[2002,9,30]],"date-time":"2002-09-30T13:43:21Z","timestamp":1033393401000},"page":"1292-1294","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":237,"title":["Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A"],"prefix":"10.1096","volume":"16","author":[{"given":"Maria L.","family":"Mart\u00ednez\u2010Chantar","sequence":"first","affiliation":[{"name":"Division of Hepatology and Gene Therapy, Department of Medicine, School of Medicine University of Navarra  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando J.","family":"Corrales","sequence":"additional","affiliation":[{"name":"Division of Hepatology and Gene Therapy, Department of Medicine, School of Medicine University of Navarra  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. Alfonso","family":"Mart\u00ednez\u2010Cruz","sequence":"additional","affiliation":[{"name":"Division of Hepatology and Gene Therapy, Department of Medicine, School of Medicine University of Navarra  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena R.","family":"Garc\u00eda\u2010Trevijano","sequence":"additional","affiliation":[{"name":"Division of Hepatology and Gene Therapy, Department of Medicine, School of Medicine University of Navarra  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zong\u2010Zhi","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Liver Diseases, USC\u2010UCLA Research Center for Alcoholic Liver and Pancreatic Diseases USC Liver Disease Research Center, USC School of Medicine  Los Angeles CA 90033 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Liver Diseases, USC\u2010UCLA Research Center for Alcoholic Liver and Pancreatic Diseases USC Liver Disease Research Center, USC School of Medicine  Los Angeles CA 90033 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Kanel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Rancho Los Amigos Keck School of Medicine USC  Los Angeles CA 90033 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mat\u00edas A.","family":"Avila","sequence":"additional","affiliation":[{"name":"Division of Hepatology and Gene Therapy, Department of Medicine, School of Medicine University of Navarra  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Mato","sequence":"additional","affiliation":[{"name":"Division of Hepatology and Gene Therapy, Department of Medicine, School of Medicine University of Navarra  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelly C.","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Liver Diseases, USC\u2010UCLA Research Center for Alcoholic Liver and Pancreatic Diseases USC Liver Disease Research Center, USC School of Medicine  Los Angeles CA 90033 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2002,6,7]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.44.070175.002251"},{"key":"e_1_2_6_3_1","first-page":"47","volume-title":"Homocysteine in Health and Disease","author":"Mato J.M.","year":"2001"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.106.2763.589"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840080113"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(00)80122-1"},{"key":"e_1_2_6_7_1","first-page":"223","article-title":"Lipotropic factors and oncogenesis","volume":"206","author":"Newberne P.M.","year":"1986","journal-title":"Adv. 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