S-Adenosylmethionine regulates MAT1A and MAT2A gene expression in culturedrat hepatocytes: a new role for S-adenosylmethionine in the maintenance ofthe differentiated status of the liver

Methionine metabolism starts with the formation of S-adenosylmethionine (Ad oMet), the most important biological methyl donor. This reaction is catalyz ed by methionine adenosyltransferase (MAT). MAT is the product of two diffe rent genes: MAT1A, which is expressed only in the adult liver, and 2MAT2A, which is widely distributed, expressed in the fetal liver, and replaces MAT 1A in hepatocarcinoma. In the liver, preservation of high expression of MAT 1A and low expression of MAT2A is critical for the maintenance of a functio nal and differentiated organ. Here we describe that in cultured rat hepatoc ytes MAT1A expression progressively decreased, as described for other liver -specific genes, and MAT2A expression was induced. We find that this switch in gene expression was prevented by adding AdoMet to the culture medium. W e also show that in cultured hepatocytes with decreased MAT1A expression Ad oMet addition markedly increased MAT1A transcription in a dose-dependent fa shion. This effect of AdoMet was mimicked by methionine, and blocked by 3-d eazaadenosine and L-ethionine, but not D-ethionine, indicating that the eff ect was specific and mediated probably by a methylation reaction. These fin dings identify AdoMet as a key molecule that differentially regulates MAT1A and MAT2A expression and helps to maintain the differentiated status of th e hepatocyte.