ArticleRole of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer
Introduction
Individuals who abuse alcohol on a chronic basis are predisposed to the development of hepatocellular carcinoma (HCC), but the molecular mechanisms are unknown. Although ethanol is not considered to be carcinogenic to the liver, it is thought to enhance the tumorigenic process. This review focuses on the possible role of two changes that occur in alcoholic liver disease, namely decreased methionine adenosyltransferase 1A (MAT1A) expression and S-adenosylmethionine (SAMe) levels, in the development of liver cancer.
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S-adenosylmethionine biosynthesis and hepatic methionine metabolism
The liver is the main source of SAMe biosynthesis and consumption, turning over nearly 8 g per day in a healthy adult (Mudd et al., 1980). S-adenosylmethionine biosynthesis is the first step in methionine metabolism in a reaction catalyzed by methionine adenosyltransferase (MAT) (Mato et al., 2002). In mammals, this reaction in the liver catabolizes nearly half the daily intake of methionine (Fig. 1). S-adenosylmethionine is the principal biologic methyl donor, the precursor for polyamine
Methionine adenosyltransferase genes and enzyme isoforms
Methionine adenosyltransferase is a critical cellular enzyme because it catalyzes the only reaction that generates SAMe (Mato el al., 2002). In mammals, two different genes, MAT1A and MAT2A, encode for two homologous MAT catalytic subunits, α1 and α2 (Kotb et al., 1997). MAT1A is expressed mostly in the liver, and it encodes the α1 subunit found in two native MAT isozymes, which are either a dimer (MAT III) or tetramer (MAT I) of this single subunit (Kotb et al., 1997). MAT2A encodes for a
Alteration in methionine adenosyltransferase expression and S-adenosylmethionine levels in alcoholic liver injury
Abnormal methionine metabolism is well known in alcoholic liver injury, and decreased hepatic SAMe levels were reported in baboons and micropigs fed ethanol (Lieber et al., 1990, Tsukamoto and Lu, 2001, Villanueva and Halsted, 2004). Because a change in hepatic MAT expression can affect the steady state SAMe level, methylation status, and cell growth, we and collaborators in our laboratory examined these variables using the Tsukamoto–French intragastric ethanol feeding model (Lu et al., 2000).
Consequences of chronic hepatic S-adenosylmethionine depletion: lessons learned from the MAT1A knockout mouse model
We and collaborators in our laboratory have developed the MAT1A knockout mouse model to address the role of MAT1A in liver injury and growth, as well as the consequences of chronic hepatic SAMe depletion (Lu et al., 2001). The MAT1A knockout mice have markedly increased serum methionine levels, as well as reduced hepatic SAMe (76% lower) and GSH (40% lower) levels (Lu et al., 2001). This finding confirms the importance of MAT1A in methionine catabolism and the influence of MAT expression on
S-adenosylmethionine regulation of hepatocyte growth
Cellular levels of SAMe seem to be related to the differentiation status of the hepatocyte. Quiescent and proliferating hepatocytes display different SAMe contents, being lower in the growing cells (Cai et al., 1998). This has been observed in rat liver after partial hepatectomy, in which SAMe levels are dramatically reduced shortly after the intervention, coinciding with the onset of DNA synthesis and the induction of early-response genes (Huang et al., 1998). When this decrease in SAMe level
S-adenosylmethionine regulation of hepatocyte death
S-adenosylmethionine regulates both the growth response and the death response of the hepatocyte. Cell death by apoptosis contributes to the development of many liver injuries that are palliated by SAMe treatment. Hence, it was important to address directly the effect of SAMe on apoptosis. We and collaborators in our laboratory found that, although SAMe protected against okadaic acid–induced apoptosis in normal hepatocytes by blocking cytochrome c release, it induced apoptosis in the liver
Use of S-adenosylmethionine in the treatment of alcoholic liver disease and direction for future research
S-adenosylmethionine administration protects against various liver injuries in animals and human beings (Mato et al., 1999, Mato et al., 2002). However, the mechanism of SAMe's protective action remains obscure. Various mechanisms, including increased GSH levels, a change in DNA methylation, improved membrane fluidity, and decreased TNF-α expression, have been proposed for the protective action of SAMe (Chawla et al., 1998, Colell et al., 1997, Lieber et al., 1990, Pascale et al., 1992, Watson
Acknowledgments
This work was supported by NIH grants DK51719 (to S. C. Lu); AA12677, AA013847, and AT1576 (to S. C. Lu and J. M. Mato); P50 AA11999 (USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases); and P30 DK48522 (USC Research Center for Liver Diseases); as well as by Plan Nacional of I+D SAF2002-00168 of the Ministerio de Educación y Ciencia (to J. M. Mato).
References (77)
- et al.
S-adenosylmethionine and methylthioadenosine are antiapoptotic in cultured rat hepatocytes but proapoptotic in human hepatoma cells
Hepatology
(2002) - et al.
Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma
J Hepatol
(2000) - et al.
Regulation of rat liver S-adenosylmethionine synthetase during septic shock: role of nitric oxide
Hepatology
(1997) - et al.
Changes in S-adenosylmethionine synthetase in human liver cancer: molecular characterization and significance
Hepatology
(1996) - et al.
Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: effect of membrane physical properties and S-adenosyl-l-methionine
Hepatology
(1997) - et al.
Effect of dietary methyl group deficiency on one-carbon metabolism in rats
J Nutr
(1989) - et al.
Effects of 5′deoxy-5′-methylthioadenosine on the metabolism of S-adenosyl methionine
Biochem Biophys Res Commun
(1983) Methionine metabolism in mammals
J Nutr Biochem
(1990)- et al.
NO sensitizes rat hepatocytes to proliferation by modifying S-adenosylmethionine levels
Gastroenterology
(2002) - et al.
Differential expression pattern of S-adenosylmethionine synthetase isoenzymes during rat liver development
Hepatology
(1996)
Expression and functional interaction of the catalytic and regulatory subunits of human methionine adenosyltransferase in mammalian cells
J Biol Chem
S-adenosylmethionine and S-adenosylhomocysteine metabolism in isolated rat liver. Effects of l-methionine, l-homocysteine, and adenosine
J Biol Chem
Immunohistochemical analysis of rat S-adenosylmethionine synthetase isozymes in developmental liver
FEBS Lett
Molecular cloning and nucleotide sequence of cDNA encoding the rat kidney S-adenosylmethionine synthetase
J Biol Chem
Molecular cloning and developmental expression of a human kidney S-adenosylmethionine synthetase
FEBS Lett
Evidence for impairment of transsulfuration pathway in cirrhosis
Gastroenterology
Prohibitin, an antiproliferative protein, is localized to mitochondria
FEBS Lett
S-Adenosylmethionine synthetase from human lymphocytes. Purification and characterization
J Biol Chem
Consensus nomenclature for the mammalian methionine adenosyltransferase genes and gene products
Trends Genet
Cloning, expression, and functional characterization of the β regulatory subunit of human methionine adenosyltransferase (MAT II)
J Biol Chem
Methionine adenosyltransferase II β subunit gene expression provides a proliferative advantage in human hepatoma
Gastroenterology
l-Methionine availability regulates expression of the methionine adenosyltransferase 2A gene in human hepatocarcinoma cells
J Biol Chem
S-Adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind multicenter clinical trial
J Hepatol
Labile methyl group balances in the human: the role of sarcosine
Metabolism
Nitric oxide production by cells isolated from regenerating rat liver
Biochem Biophys Res Commun
Modulation of rat liver S-adnosylmethionine synthetase activity by glutathione
J Biol Chem
5′-Methylthioadenosine administration prevents lipid peroxidation and fibrogenesis induced in rat liver by carbon-tetrachloride intoxication
J Hepatol
Antibodies to tumor necrosis factor-α inhibit liver regeneration after partial hepatectomy
Am J Physiol
Characterization of a full-length cDNA encoding human liver S-adenosylmethionine synthetase: tissue-specific gene expression and mRNA levels in hepatopathies
Biochem J
Alterations in DNA methylation: a fundamental aspect of neoplasia
Adv Cancer Res
The effect of lecithin on fat deposition in the liver of the normal rat
J Physiol
Purification and comparison of two forms of S-adenoysl-l-methionine synthetase from rat liver
Eur J Biochem
Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells
Cancer Res
S-adenosylmethione deficiency and TNF-α in lipopolysaccharide-induced hepatic injury
Am J Physiol
Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice
Science
Inhibition of promotion and persistent nodule growth by S-adenosyl-l-methionine in rat liver carcinogenesis: role of remodeling and apoptosis
Cancer Res
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
FASEB J
5′-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes
Hepatology
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