ABSTRACT
Introduction ............................................................................................................ 104 The Methionine Metabolic Pathway ...................................................................... 104 Methionine Adenosyltransferases .......................................................................... 105
MAT Structure and Properties ........................................................................... 105 MAT Expression and Subcellular Localization................................................. 105 MAT Protein Modications............................................................................... 106
MAT Dysregulation in HCC Development ............................................................ 107 Mechanisms of MAT1A Silencing during HCC ................................................ 107 Consequences of Hepatic MAT1A Downregulation in Liver ............................ 108
Oxidative Stress ............................................................................................ 109 Altered Lipid Homeostasis ........................................................................... 109 Genotoxic Stress ........................................................................................... 109 Deregulated Growth Signaling ..................................................................... 110
Restoration of MAT1A Expression in HCC ....................................................... 112 Mechanisms of MAT2A/MAT2B Deregulation during HCC ............................. 112
MAT Deregulation in Liver Fibrosis/Cirrhosis ...................................................... 114 MAT1A Silencing during Liver Cirrhosis .......................................................... 115 MAT2A and MAT2B Deregulation in Liver Fibrosis/Cirrhosis ......................... 115 Mechanisms of MAT2A and MAT2B Deregulation during HSC Activation ..... 116
Summary and Future Directions ............................................................................ 117 Acknowledgments .................................................................................................. 118 References .............................................................................................................. 118
Methionine is an essential amino acid whose metabolism in the liver is mediated by its conversion to S-adenosylmethionine (AdoMet), the methyl donor in mammalian cells. This reaction is catalyzed by methionine adenosyltransferases (MAT) (Lu and Mato, 2012). Three types of MAT proteins, MATα1, MATα2, and MATβ are encoded by MAT1A, MAT2A, and MAT2B genes, respectively (Mato et al., 2002). Variations in the expression of MAT isoenzymes have a long-standing relationship with liver diseases such as nonalcoholic steatohepatitis (NASH) (MartínezChantar et al., 2002a), liver cirrhosis (Martin-Duce et al., 1988), and hepatocellular carcinoma (HCC) (Cai et al., 1998). Mutations in the human MAT1A gene have been linked to hepatic MAT deciency (OMIM number 250850), an inborn error of methionine metabolism in which patients have presented with isolated persistent hypermethioninemia (Gaull et al., 1981). In this chapter, we will describe the current knowledge on regulation and function of MAT genes in normal and diseased liver.
