Elsevier

Alcohol

Volume 35, Issue 3, April 2005, Pages 227-234
Alcohol

Article
Role of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer

https://doi.org/10.1016/j.alcohol.2005.03.011Get rights and content

Abstract

Two genes (MAT1A and MAT2A) encode for the essential enzyme methionine adenosyltransferase (MAT), which catalyzes the biosynthesis of S-adenosylmethionine (SAMe), the principal methyl donor and, in the liver, a precursor of glutathione. MAT1A is expressed mostly in the liver, whereas MAT2A is widely distributed. MAT2A is induced in the liver during periods of rapid growth and dedifferentiation. In human hepatocellular carcinoma (HCC) MAT1A is replaced by MAT2A. This is important pathogenetically because MAT2A expression is associated with lower SAMe levels and faster growth, whereas exogenous SAMe treatment inhibits growth. Rats fed ethanol intragastrically for 9 weeks also exhibit a relative switch in hepatic MAT expression, decreased SAMe levels, hypomethylation of c-myc, increased c-myc expression, and increased DNA strand break accumulation. Patients with alcoholic liver disease have decreased hepatic MAT activity owing to both decreased MAT1A expression and inactivation of the MAT1A-encoded isoenzymes, culminating in decreased SAMe biosynthesis. Consequences of chronic hepatic SAMe depletion have been examined in the MAT1A knockout mouse model. In this model, the liver is more susceptible to injury. In addition, spontaneous steatohepatitis develops by 8 months, and HCC develops by 18 months. Accumulating evidence shows that, in addition to being a methyl donor, SAMe controls hepatocyte growth response and death response. Whereas transient SAMe depletion is necessary for the liver to regenerate, chronic hepatic SAMe depletion may lead to malignant transformation. It is interesting that SAMe is antiapoptotic in normal hepatocytes, but proapoptotic in liver cancer cells. This should make SAMe an attractive agent for both chemoprevention and treatment of HCC.

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.

Section snippets

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).

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