Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation

Liver-specific and nonliver-specific methionine adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A, respectively, that catalyze th e formation of S-adenosylmethionine (AdoMet), the principal biological meth yl donor. Mature liver expresses MAT1A, whereas MAT2A is expressed in extra hepatic tissues and is induced during liver growth and dedifferentiation. T o examine the influence of MAT1A on hepatic growth, we studied the effects of a targeted disruption of the murine MAT1A gene. MAT1A mRNA and protein l evels were absent in homozygous knockout mice. At 3 months, plasma methioni ne level increased 776% in knockouts. Hepatic AdoMet and glutathione levels were reduced by 74 and 40%, respectively, whereas S-adenosylhomocysteine, methylthioadenosine, and global DNA methylation were unchanged. The body we ight of 3-month-old knockout mice was unchanged from wild-type littermates, but the liver weight was increased 40%. The Affymetrix GENECHIP system and Northern and Western blot analyses were used to analyze differential expre ssion of genes. The expression of many acute phase-response and inflammator y markers, including orosomucoid, amyloid, metallothionein, Fas antigen, an d growth-related genes, including early growth response 1 and proliferating cell nuclear antigen, is increased in the knockout animal. At 3 months, kn ockout mice are more susceptible to choline-deficient diet-induced fatty li ver. At 8 months, knockout mice developed spontaneous macrovesicular steato sis and predominantly periportal mononuclear cell infiltration. Thus, absen ce of MAT1A resulted in a liver that is more susceptible to injury, express es markers of an acute phase response, and displays increased proliferation .