Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation

DOI Web Site 8 Citations
  • Shelly C. Lu
    Liver Disease Research Center, Research Center for Alcoholic Liver and Pancreatic Diseases, and Department of Pathology, Rancho Los Amigos, Keck School of Medicine, University of Southern California–University of California, Los Angeles, CA 90033; Servicio de Cirugía Experimental, Hospital Universitario “La Paz”, Madrid, Spain; and Division of Hepatology and Gene Therapy, University of Navarra School of Medicine, 31008 Pamplona, Spain
  • Luis Alvarez
    Liver Disease Research Center, Research Center for Alcoholic Liver and Pancreatic Diseases, and Department of Pathology, Rancho Los Amigos, Keck School of Medicine, University of Southern California–University of California, Los Angeles, CA 90033; Servicio de Cirugía Experimental, Hospital Universitario “La Paz”, Madrid, Spain; and Division of Hepatology and Gene Therapy, University of Navarra School of Medicine, 31008 Pamplona, Spain
  • Zong-Zhi Huang
    Liver Disease Research Center, Research Center for Alcoholic Liver and Pancreatic Diseases, and Department of Pathology, Rancho Los Amigos, Keck School of Medicine, University of Southern California–University of California, Los Angeles, CA 90033; Servicio de Cirugía Experimental, Hospital Universitario “La Paz”, Madrid, Spain; and Division of Hepatology and Gene Therapy, University of Navarra School of Medicine, 31008 Pamplona, Spain
  • Lixin Chen
    Liver Disease Research Center, Research Center for Alcoholic Liver and Pancreatic Diseases, and Department of Pathology, Rancho Los Amigos, Keck School of Medicine, University of Southern California–University of California, Los Angeles, CA 90033; Servicio de Cirugía Experimental, Hospital Universitario “La Paz”, Madrid, Spain; and Division of Hepatology and Gene Therapy, University of Navarra School of Medicine, 31008 Pamplona, Spain
  • Wei An
    Liver Disease Research Center, Research Center for Alcoholic Liver and Pancreatic Diseases, and Department of Pathology, Rancho Los Amigos, Keck School of Medicine, University of Southern California–University of California, Los Angeles, CA 90033; Servicio de Cirugía Experimental, Hospital Universitario “La Paz”, Madrid, Spain; and Division of Hepatology and Gene Therapy, University of Navarra School of Medicine, 31008 Pamplona, Spain
  • Fernando J. Corrales
    Liver Disease Research Center, Research Center for Alcoholic Liver and Pancreatic Diseases, and Department of Pathology, Rancho Los Amigos, Keck School of Medicine, University of Southern California–University of California, Los Angeles, CA 90033; Servicio de Cirugía Experimental, Hospital Universitario “La Paz”, Madrid, Spain; and Division of Hepatology and Gene Therapy, University of Navarra School of Medicine, 31008 Pamplona, Spain
  • Matías A. Avila
    Liver Disease Research Center, Research Center for Alcoholic Liver and Pancreatic Diseases, and Department of Pathology, Rancho Los Amigos, Keck School of Medicine, University of Southern California–University of California, Los Angeles, CA 90033; Servicio de Cirugía Experimental, Hospital Universitario “La Paz”, Madrid, Spain; and Division of Hepatology and Gene Therapy, University of Navarra School of Medicine, 31008 Pamplona, Spain
  • Gary Kanel
    Liver Disease Research Center, Research Center for Alcoholic Liver and Pancreatic Diseases, and Department of Pathology, Rancho Los Amigos, Keck School of Medicine, University of Southern California–University of California, Los Angeles, CA 90033; Servicio de Cirugía Experimental, Hospital Universitario “La Paz”, Madrid, Spain; and Division of Hepatology and Gene Therapy, University of Navarra School of Medicine, 31008 Pamplona, Spain
  • José M. Mato
    Liver Disease Research Center, Research Center for Alcoholic Liver and Pancreatic Diseases, and Department of Pathology, Rancho Los Amigos, Keck School of Medicine, University of Southern California–University of California, Los Angeles, CA 90033; Servicio de Cirugía Experimental, Hospital Universitario “La Paz”, Madrid, Spain; and Division of Hepatology and Gene Therapy, University of Navarra School of Medicine, 31008 Pamplona, Spain

Abstract

<jats:p> Liver-specific and nonliver-specific methionine adenosyltransferases (MATs) are products of two genes, <jats:italic>MAT1A</jats:italic> and <jats:italic>MAT2A</jats:italic> , respectively, that catalyze the formation of <jats:italic>S</jats:italic> -adenosylmethionine (AdoMet), the principal biological methyl donor. Mature liver expresses <jats:italic>MAT1A</jats:italic> , whereas <jats:italic>MAT2A</jats:italic> is expressed in extrahepatic tissues and is induced during liver growth and dedifferentiation. To examine the influence of <jats:italic>MAT1A</jats:italic> on hepatic growth, we studied the effects of a targeted disruption of the murine <jats:italic>MAT1A</jats:italic> gene. <jats:italic>MAT1A</jats:italic> mRNA and protein levels were absent in homozygous knockout mice. At 3 months, plasma methionine level increased 776% in knockouts. Hepatic AdoMet and glutathione levels were reduced by 74 and 40%, respectively, whereas <jats:italic>S</jats:italic> -adenosylhomocysteine, methylthioadenosine, and global DNA methylation were unchanged. The body weight of 3-month-old knockout mice was unchanged from wild-type littermates, but the liver weight was increased 40%. The Affymetrix <jats:sc>genechip</jats:sc> system and Northern and Western blot analyses were used to analyze differential expression of genes. The expression of many acute phase-response and inflammatory markers, including orosomucoid, amyloid, metallothionein, Fas antigen, and growth-related genes, including early growth response 1 and proliferating cell nuclear antigen, is increased in the knockout animal. At 3 months, knockout mice are more susceptible to choline-deficient diet-induced fatty liver. At 8 months, knockout mice developed spontaneous macrovesicular steatosis and predominantly periportal mononuclear cell infiltration. Thus, absence of <jats:italic>MAT1A</jats:italic> resulted in a liver that is more susceptible to injury, expresses markers of an acute phase response, and displays increased proliferation. </jats:p>

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