The Importance of MAT and SAM in Liver Disease and Cancer

Dr.Shelly C. Lu

Division of Gastrointestinal and Liver Diseases, Keck School of Medicine
University of Southern California

The Importance of MAT and SAM in Liver Disease and Cancer

A brief abstract:

Methionine is an essential amino acid metabolized mainly by the liver where it is converted, by the enzyme methionine adenosyltransferase (MAT), into S-adenosylmethionine (SAM), the main biological methyl donor, precursor for polyamines and GSH. About 50% of methionine metabolism and up to 85% of all methylation reactions occur in the liver. In mammals there are two genes encoding MAT isoenzymes: MAT I/III are gene products of MAT1A and MAT II is the gene product of MAT2A. While MAT1A is expressed mainly in the adult liver and is a marker for differentiated liver, MAT2A is expressed in all tissues including fetal liver, hepatocellular carcinoma (HCC) and in small quantities, the adult liver.  MAT2A is up-regulated during rapid liver growth and de-differentiation. Due to differences in the regulatory and kinetic properties of the various MATs, MAT II cannot maintain the same high levels of SAM as compared to the combination of MAT I and MAT III. Thus, the type of MAT expressed by the cell can influence the steady state SAM level.  Besides the well-known metabolic pathways for which SAM participates, recent work shows that SAM also modulates hepatocyte growth, differentiation and apoptosis. SAM helps turn off the hepatocyte's response to growth factors, and without this protection, steatohepatitis and malignant degeneration may take place. The medical implications of these observations are obvious, since cirrhotic patients have impaired hepatic synthesis of SAM and are predisposed to the development of liver cancer.