S‐Adenosylmethionine: a control switch that regulates liver function

Genome sequence analysis reveals that all organisms synthesize S‐adenosylmethionine (AdoMet) and that a large fraction of all genes is AdoMet‐dependent methyltransferases. AdoMet‐dependent methylation has been shown to be central to many biological processes. Up to 85% of all methylation reactions and as much as 48% of methionine metabo‐lism occur in the liver, which indicates the crucial importance of this organ in the regulation of blood methionine. Of the two mammalian genes (MAT1A, MAT2A) that encode methionine adenosyltransferase (MAT, the enzyme that makes AdoMet), MAT1A is specifically expressed in adult liver. It now appears that growth factors, cytokines, and hormones regulate liver MAT mRNA levels and enzyme activity and that AdoMet should not be viewed only as an intermediate metabolite in methionine catabolism, but also as an intracellular control switch that regulates essential he‐patic functions such as regeneration, differentiation, and the sensitivity of this organ to injury. The aim of this review is to integrate these recent findings linking AdoMet with liver growth, differentiation, and injury into a comprehensive model. With the availability of AdoMet as a nutritional supplement and evidence of its beneficial role in various liver diseases, this review offers insight into its mechanism of action.—Mato, J. M., Corrales, F. J., Lu, S. C., Avila, M. A. S‐Adenosylmethionine: a control switch that regulates liver function. FASEB J. 16, 15–26 (2002)

[1]  F. Corrales,et al.  Biochemical basis for the dominant inheritance of hypermethioninemia associated with the R264H mutation of the MAT1A gene. A monomeric methionine adenosyltransferase with tripolyphosphatase activity. , 2001, The Journal of biological chemistry.

[2]  F. Corrales,et al.  Nitric oxide inactivates rat hepatic methionine adenosyltransferase in vivo by S‐nitrosylation , 1998, Hepatology.

[3]  Shelly C. Lu,et al.  Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  L. Boscá,et al.  Regulation of rat liver S‐adenosylmethionine synthetase during septic shock: Role of nitric oxide , 1997, Hepatology.

[5]  M. Kotb,et al.  Cloning, Expression, and Functional Characterization of the β Regulatory Subunit of Human Methionine Adenosyltransferase (MAT II)* , 2000, The Journal of Biological Chemistry.

[6]  A. Kato,et al.  Regulation of cyclin D-dependent kinase activity in rat liver regeneration. , 1998, Biochemical and biophysical research communications.

[7]  M. Kotb,et al.  Regulation of the Human MAT2B Gene Encoding the Regulatory β Subunit of Methionine Adenosyltransferase, MAT II* , 2001, The Journal of Biological Chemistry.

[8]  E. Stokstad,et al.  Feedback inhibition of methylene-tetrahydrofolate reductase in rat liver by S-adenosylmethionine. , 1967, Biochimica et biophysica acta.

[9]  M. Huntsman,et al.  The effect of lecithine on fat deposition in the liver of the normal rat , 1932, The Journal of physiology.

[10]  M. Ingelman-Sundberg,et al.  Modulation of experimental alcohol-induced liver disease by cytochrome P450 2E1 inhibitors. , 1995, Hepatology.

[11]  J. Finkelstein,et al.  Methionine metabolism in mammals. , 1990, The Journal of nutritional biochemistry.

[12]  C. Allis,et al.  Signaling to Chromatin through Histone Modifications , 2000, Cell.

[13]  M. Pajares,et al.  Analysis of the 5′ non‐coding region of rat liver S‐adenosylmethionine synthetase mRNA and comparison of the M r deduced from the cDNA sequence and the purified enzyme , 1991, FEBS letters.

[14]  Eric J. Toone,et al.  (S)NO Signals: Translocation, Regulation, and a Consensus Motif , 1997, Neuron.

[15]  M. Pajares,et al.  Modulation of rat liver S-adenosylmethionine synthetase activity by glutathione. , 1992, The Journal of biological chemistry.

[16]  J. Peters,et al.  CYP2E1 is not involved in early alcohol-induced liver injury. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[17]  J. Chou.  Molecular genetics of hepatic methionine adenosyltransferase deficiency. , 2000, Pharmacology & therapeutics.

[18]  I. Leclercq,et al.  Altered expression of hepatic CYP2E1 and CYP4A in obese, diabetic ob/ob mice, and fa/fa Zucker rats. , 1999, Biochemical and biophysical research communications.

[19]  M. Ingelman-Sundberg,et al.  Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis , 1998, Hepatology.

[20]  M. Kotb,et al.  Consensus nomenclature for the mammalian methionine adenosyltransferase genes and gene products. , 1997, Trends in genetics : TIG.

[21]  F. Corrales,et al.  Hysteretic Behavior of Methionine Adenosyltransferase III , 2000, The Journal of Biological Chemistry.

[22]  Shelly C. Lu.  Regulation of hepatic glutathione synthesis: current concepts and controversies , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[23]  P. Newberne,et al.  Lipotropic factors and oncogenesis. , 1986, Advances in experimental medicine and biology.

[24]  S. Mudd,et al.  Labile methyl balances for normal humans on various dietary regimens. , 1975, Metabolism: clinical and experimental.

[25]  Yosef Yarden,et al.  Molecular mechanisms underlying ErbB2/HER2 action in breast cancer , 2000, Oncogene.

[26]  Shelly C. Lu,et al.  Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. , 1998, Cancer research.

[27]  G. Cantoni.  Biological methylation: selected aspects. , 1975, Annual review of biochemistry.

[28]  I. Leclercq,et al.  CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. , 2000, The Journal of clinical investigation.

[29]  C. Lowenstein,et al.  Impaired liver regeneration in inducible nitric oxide synthasedeficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  H. Yang,et al.  The role of c-Myb and Sp1 in the up-regulation of methionine adenosyltransferase 2A gene expression in human hepatocellular carcinoma. , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  B. González,et al.  The crystal structure of tetrameric methionine adenosyltransferase from rat liver reveals the methionine-binding site. , 2000, Journal of molecular biology.

[32]  Shelly C. Lu,et al.  Hepatocyte growth factor induces MAT2A expression and histone acetylation in rat hepatocytes: role in liver regeneration 1 , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  Z. Huang,et al.  Cloning and functional characterization of the 5'-flanking region of human methionine adenosyltransferase 2A gene. , 1998, Biochemical and biophysical research communications.

[34]  M. Kotb,et al.  Differential Regulation of Methionine Adenosyltransferase in Superantigen and Mitogen Stimulated Human T Lymphocytes* , 1997, The Journal of Biological Chemistry.

[35]  M. Avila,et al.  S‐Adenosylmethionine regulates MAT1A and MAT2A gene expression in cultured rat hepatocytes: a new role for S‐adenosylmethionine in the maintenance of the differentiated status of the liver , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[36]  J. Rodés,et al.  S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. , 1999, Journal of hepatology.

[37]  M. Pajares,et al.  Glucocorticoid Regulation of Hepatic S-Adenosylmethionine Synthetase Gene Expression * , 1997 .

[38]  F. Corrales,et al.  Methionine Adenosyltransferase S-Nitrosylation Is Regulated by the Basic and Acidic Amino Acids Surrounding the Target Thiol* , 1999, The Journal of Biological Chemistry.

[39]  T. Nezu,et al.  A Novel NDP-6-deoxyhexosyl-4-ulose Reductase in the Pathway for the Synthesis of Thymidine Diphosphate-d-fucose* , 1999, The Journal of Biological Chemistry.

[40]  K. Tsukada,et al.  Structure of the rat methionine adenosyltransferase 2A gene and its promoter. , 1997, European journal of biochemistry.

[41]  J. Finkelstein,et al.  Methionine metabolism in mammals. Distribution of homocysteine between competing pathways. , 1984, The Journal of biological chemistry.

[42]  A. Pick,et al.  Activation of cystathionine synthase by adenosylmethionine and adenosylethionine. , 1975, Biochemical and biophysical research communications.

[43]  C. W. Tabor,et al.  S-Adenosylmethionine synthetase from Escherichia coli. , 1980, The Journal of biological chemistry.

[44]  D. Horne,et al.  Effect of dietary methyl group deficiency on one-carbon metabolism in rats. , 1989, The Journal of nutrition.

[45]  A. Cederbaum,et al.  Stable expression of human cytochrome P4502E1 in HepG2 cells: characterization of catalytic activities and production of reactive oxygen intermediates. , 1993, Biochemistry.

[46]  P. Sperryn,et al.  Blood. , 1989, British journal of sports medicine.

[47]  J. Albrecht,et al.  Cyclin D1 promotes mitogen-independent cell cycle progression in hepatocytes. , 1999, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[48]  Shelly C. Lu,et al.  Changes in methionine adenosyltransferase during liver regeneration in the rat. , 1998, American journal of physiology. Gastrointestinal and liver physiology.

[49]  H. Yang,et al.  Cloning and functional characterization of the 5'-flanking region of human methionine adenosyltransferase 1A gene. , 2000, The Biochemical journal.

[50]  Shelly C. Lu,et al.  Liver‐specific methionine adenosyltransferase MAT1A gene expression is associated with a specific pattern of promoter methylation and histone acetylation: implications for MAT1A silencing during transformation , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[51]  Yongbo Hu,et al.  Flexible loop in the structure of S-adenosylmethionine synthetase crystallized in the tetragonal modification. , 1996, Journal of biomolecular structure & dynamics.

[52]  J. Viña,et al.  Increased sensitivity to oxidative injury in chinese hamster ovary cells stably transfected with rat liver S-adenosylmethionine synthetase cDNA. , 1996, The Biochemical journal.

[53]  Shelly C. Lu,et al.  Current Concepts in the Pathogenesis of Alcoholic Liver Injury , 2022 .

[54]  M. Pajares,et al.  Differential expression pattern of S‐adenosylmethionine synthetase isoenzymes during rat liver development , 1996, Hepatology.

[55]  H. Yang,et al.  The role of c-Myb in the up-regulation of methionine adenosyltransferase 2A expression in activated Jurkat cells. , 2001, The Biochemical journal.

[56]  H. Olle,et al.  Putrescine, Spermidine, and Spermine , 1986 .

[57]  L. Franco,et al.  DNA methylation and histone acetylation of rat methionine adenosyltransferase 1A and 2A genes is tissue-specific. , 2000, The international journal of biochemistry & cell biology.

[58]  V. Marras,et al.  Chemoprevention of rat liver carcinogenesis by S-adenosyl-L-methionine: a long-term study. , 1992, Cancer research.

[59]  J. Hwang,et al.  Changes in S‐adenosylmethionine synthetase in human liver cancer: Molecular characterization and significance , 1996, Hepatology.

[60]  F. Corrales,et al.  Interaction of liver methionine adenosyltransferase with hydroxyl radical , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[61]  S. Kamitori,et al.  Crystal Structure of S-Adenosylmethionine Synthetase (*) , 1996, The Journal of Biological Chemistry.

[62]  V. P. Chacko,et al.  Hepatic hyperplasia in noncirrhotic fatty livers: is obesity-related hepatic steatosis a premalignant condition? , 2001, Cancer research.

[63]  C. W. Tabor,et al.  1,4-Diaminobutane (putrescine), spermidine, and spermine. , 1976, Annual review of biochemistry.

[64]  G. Cantoni.  Activation of methionine for transmethylation. , 1951, The Journal of biological chemistry.

[65]  L. Gaspa,et al.  Inhibition of promotion and persistent nodule growth by S-adenosyl-L-methionine in rat liver carcinogenesis: role of remodeling and apoptosis. , 1989, Cancer research.

[66]  F. Corrales,et al.  In vivo regulation by glutathione of methionine adenosyltransferase S-nitrosylation in rat liver. , 1999, Journal of hepatology.

[67]  J. Finkelstein,et al.  Homocysteine: a history in progress. , 2009, Nutrition reviews.

[68]  S. Alemany,et al.  Specific loss of the high‐molecular‐weight form of S‐adenosyl‐L‐methionine synthetase in human liver cirrhosis , 1988, Hepatology.

[69]  Shelly C. Lu,et al.  Changes in methionine adenosyltransferase and S-adenosylmethionine homeostasis in alcoholic rat liver. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[70]  J. Mato,et al.  S‐adenosyl‐L‐methionine synthetase and phospholipid methyltransferase are inhibited in human cirrhosis , 1988, Hepatology.

[71]  J. J. Martin,et al.  Inactivation of betaine-homocysteine methyltransferase by adenosylmethionine and adenosylethionine. , 1984, Biochemical and biophysical research communications.

[72]  M. Pajares,et al.  Characterization of Rat Liver-specific Methionine Adenosyltransferase Gene Promoter , 1997, The Journal of Biological Chemistry.

[73]  C. Lieber.  Role of S-adenosyl-L-methionine in the treatment of liver diseases. , 1999, Journal of hepatology.

[74]  N. Kojima,et al.  Differential expression of S‐adenosylmethionine synthetase isozymes in different cell types of rat liver , 1997, Hepatology.

[75]  M. Pajares,et al.  S-adenosylmethionine synthesis: molecular mechanisms and clinical implications. , 1997, Pharmacology & therapeutics.

[76]  E. Stokstad,et al.  Mammalian methylenetetrahydrofolate reductase. Partial purification, properties, and inhibition by S-adenosylmethionine. , 1971, Biochimica et biophysica acta.

[77]  Shelly C. Lu,et al.  Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. , 2000, Journal of hepatology.

[78]  A. Cederbaum,et al.  CYP2E1 Overexpression in HepG2 Cells Induces Glutathione Synthesis by Transcriptional Activation of γ-Glutamylcysteine Synthetase* , 2000, The Journal of Biological Chemistry.

[79]  M. Kotb,et al.  Methionine adenosyltransferase: structure and function. , 1993, Pharmacology & therapeutics.

[80]  Brian P. Mulhall,et al.  Nonalcoholic steatohepatitis , 2004, Current treatment options in gastroenterology.

[81]  F. Corrales,et al.  Creation of a functional S‐nitrosylation site in vitro by single point mutation , 1999, FEBS letters.

[82]  G. Michalopoulos,et al.  Liver Regeneration , 1997, Science.

[83]  L. Poirier,et al.  Tissue levels of S-adenosylmethionine and S-adenosylhomocysteine in rats fed methyl-deficient, amino acid-defined diets for one to five weeks. , 1983, Carcinogenesis.

[84]  J. Downward.  The ins and outs of signalling , 2001, Nature.

[85]  M. Kotb,et al.  Expression and Functional Interaction of the Catalytic and Regulatory Subunits of Human Methionine Adenosyltransferase in Mammalian Cells* , 1999, The Journal of Biological Chemistry.

[86]  H. Harper,et al.  Rate of disappearance from plasma of intravenously administered methionine in patients with liver damage. , 1947, Science.

[87]  M. Avila,et al.  Regulation by hypoxia of methionine adenosyltransferase activity and gene expression in rat hepatocytes. , 1998, Gastroenterology.

[88]  C. Lieber.  ALCOHOL: its metabolism and interaction with nutrients. , 2000, Annual review of nutrition.

[89]  Defeng Wu,et al.  Ethanol Cytotoxicity to a Transfected HepG2 Cell Line Expressing Human Cytochrome P4502E1* , 1996, The Journal of Biological Chemistry.

[90]  H. Yang,et al.  Role of promoter methylation in increased methionine adenosyltransferase 2A expression in human liver cancer. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[91]  R. Lorini,et al.  Glycine N-methyltransferase deficiency: A novel inborn error causing persistent isolated hypermethioninaemia , 2001, Journal of Inherited Metabolic Disease.

[92]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.

[93]  C. Lieber,et al.  Cytochrome P-4502E1: its physiological and pathological role. , 1997, Physiological reviews.