Alcohol
Volume 27, Issue 3 , Pages 155-162, July 2002

Role of abnormal methionine metabolism in alcoholic liver injury☆

  • Shelly C Lu

      Affiliations

    • Corresponding Author InformationCorresponding author. Division of Gastrointestinal and Liver Diseases, HMR Bldg., 415, Department of Medicine, USC School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033, USA. Tel.: +1-323-442-2441; fax: +1-323-442-3234.
    • USC Liver Disease Research Center, USC–UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, Los Angeles, CA 90033, USA
    • ,
  • Hidekazu Tsukamoto

      Affiliations

    • USC Liver Disease Research Center, USC–UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, Los Angeles, CA 90033, USA
    • ,
  • José M Mato

      Affiliations

    • Division of Hepatology and Gene Therapy, University of Navarra School of Medicine, 31008 Pamplona, Spain

Received 4 February 2002; received in revised form 12 April 2002; accepted 16 April 2002.

Abstract 

Methionine catabolism occurs mostly in the liver through the formation of S-adenosylmethionine (SAM) in a reaction catalyzed by methionine adenosyltransferase (MAT). S-adenosylmethionine is the principal biologic methyl donor, a precursor for polyamines, and in liver, it is also a precursor for reduced glutathione (GSH). Liver-specific and non-liver-specific MAT are products of two different genes, MAT1A and MAT2A, respectively. Mature liver expresses MAT1A, whereas MAT2A is expressed in extrahepatic tissues and induced during liver growth and de-differentiation. The type of MAT expressed by the cell affects the steady-state SAM level, DNA methylation, and growth rate. This has been demonstrated further by using the MAT1A knockout mouse model in which hepatic SAM and GSH levels decrease, the liver becomes larger and more susceptible to injury, and steatohepatitis develops spontaneously. Altered methionine metabolism in alcoholic liver disease results in decreased transmethylation and transsulfuration, changes that may play important pathogenic roles. Major changes include a relative switch in MAT expression; decreased hepatic SAM, GSH, and DNA methylation levels; decreased homocysteine metabolism; and hyperhomocysteinemia. Consequences of hepatic DNA hypomethylation include increased expression of c-myc and DNA strand break accumulation. One possible consequence of hyperhomocysteinemia is increased fibrogenesis. Abnormal methionine metabolism may also occur in Kupffer cells, which express both forms of MAT. If SAM levels also decrease in these cells, this may contribute to the induction of tumor necrosis factor (TNF) expression and release. In summary, altered hepatic methionine metabolism can have serious consequences that affect not only hepatocytes, but also hepatic stellate and Kupffer cells. These changes can lead to impaired antioxidant defense, altered gene expression, promotion of fibrogenesis, and even hepatocarcinogenesis.

Keywords:  S-adenosylmethionine, Methionine adenosyltransferase, Homocysteine, Alcoholic liver injury

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☆ Editor: T.R. Jerrells

PII: S0741-8329(02)00226-4

Alcohol
Volume 27, Issue 3 , Pages 155-162, July 2002

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