Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A
| Autor: | María L. Martínez-Chantar, Lixin Chen, Elena R. García-Trevijano, Matías A. Avila, José M. Mato, Shelly C. Lu, L. Alfonso Martínez-Cruz, Fernando J. Corrales, Zong-Zhi Huang, Gary Kanel |
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| Předmět: |
S-Adenosylmethionine
medicine.medical_specialty Methionine Adenosyltransferase/physiology Hepatitis Animal Biology Liver Neoplasms Experimental/etiology medicine.disease_cause Models Biological Biochemistry Ion Channels Malignant transformation Mitochondrial Proteins Mice Diabetes mellitus genetics chemistry.chemical_compound Liver Neoplasms Experimental Internal medicine Diabetes Mellitus Genetics medicine Animals Uncoupling Protein 2 Obesity RNA Messenger Carbon Tetrachloride Molecular Biology Mice Knockout Liver injury Methionine Gene Expression Profiling Liver Diseases Membrane Transport Proteins Proteins Cytochrome P-450 CYP2E1 Methionine Adenosyltransferase medicine.disease Gene expression profiling Oxidative Stress Endocrinology Liver chemistry Protein Biosynthesis Knockout mouse Disease Susceptibility Chemical and Drug Induced Liver Injury Oxidative stress Biotechnology |
| Zdroj: | ResearcherID Scopus-Elsevier |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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