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Dadun > Depósito Académico > CIMA (Centro de Investigación Médica Aplicada) > Área de Terapia génica y Hepatología > Hepatología bioquímica > DA - CIMA - Terapia génica y Hepatología - Hepatología bioquímica - Artículos de revista >

Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A
Authors: Martinez-Chantar, M.L. (María Luz)
Corrales, F.J. (Fernando José)
Martinez-Cruz, L.A. (L. Alfonso)
Garcia-Trevijano, E.R. (Elena R.)
Huang, Z.Z. (Zong-Zhi)
Chen, L. (L)
Kanel, G. (G)
Avila, M.A. (Matías Antonio)
Mato, J.M. (José María)
Lu, S.C. (Shelly C.)
Keywords: Liver Neoplasms, Experimental/etiology
Membrane Transport Proteins
Methionine Adenosyltransferase/physiology
Mitochondrial Proteins
Oxidative Stress
Issue Date: 2002
Publisher: Federation of American Society of Experimental Biology
Publisher version: http://www.fasebj.org/content/early/2002/08/02/fj.02-0078fje
ISSN: 1530-6860
Citation: Martinez-Chantar ML, Corrales FJ, Martinez-Cruz LA, Garcia-Trevijano ER, Huang ZZ, Chen L, et al. Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. FASEB J 2002 Aug;16(10):1292-1294.
Abstract
In mammals, methionine metabolism occurs mainly in the liver via methionine adenosyltransferase-catalyzed conversion to S-adenosylmethionine. Of the two genes that encode methionine adenosyltransferase(MAT1Aand MAT2A), MAT1A is mainly expressed in adult liver whereas MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic S-adenosylmethionine content and hyperplasia and spontaneously develop nonalcoholic steatohepatitis. In this study, we examined whether chronic hepatic S-adenosylmethionine 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-induced hepatotoxicity and malignant transformation was determined in 3- and 18-month-old 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-induced liver damage, which was largely due to increased CYP2E1 expression because diallyl sulfide, an inhibitor of CYP2E1, prevented CCl4-induced 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-adenosylmethionine in maintaining normal hepatic function and tumorigenesis of the liver.
Permanent link: http://hdl.handle.net/10171/21478
Appears in Collections:DA - CIMA - Unidad de Proteómica, Genómica y Bioinformática - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Hepatología bioquímica - Artículos de revista

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