Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A

Abstract

Methionine adenosyltransferase (MAT) is an essential enzyme because it catalyzes the formation of S-adenosylmethionine (SAMe), the principal biological methyl donor. Of the two genes that encode MAT, MAT1A is mainly expressed in adult liver and MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic SAMe content and spontaneously develop hepatocellular carcinoma. The current study examined the influence of chronic hepatic SAMe deficiency on liver regeneration. Despite having higher baseline hepatic staining for proliferating cell nuclear antigen, MAT1A knockout mice had impaired liver regeneration after partial hepatectomy (PH) as determined by bromodeoxyuridine incorporation. This can be explained by an inability to up-regulate cyclin D1 after PH in the knockout mice. Upstream signaling pathways involved in cyclin D1 activation include nuclear factor κB (NFκB), the c-Jun-N-terminal kinase (JNK), extracellular signal-regulated kinases (ERKs), and signal transducer and activator of transcription-3 (STAT-3). At baseline, JNK and ERK are more activated in the knockouts whereas NFκB and STAT-3 are similar to wild-type mice. Following PH, early activation of these pathways occurred, but although they remained increased in wildtype mice, c-jun and ERK phosphorylation fell progressively in the knockouts. Hepatic SAMe levels fell progressively following PH in wild-type mice but remained unchanged in the knockouts. In culture, MAT1A knockout hepatocytes have higher baseline DNA synthesis but failed to respond to the mitogenic effect of hepatocyte growth factor. Taken together, our findings define a critical role for SAMe in ERK signaling and cyclin D1 regulation during regeneration and suggest chronic hepatic SAMe depletion results in loss of responsiveness to mitogenic signals. ethionine is an essential amino acid metabolized mainly by the liver, where it is converted, by the enzyme methionine adenosyltransferase (MAT), into Sadenosylmethionine (SAMe), the main biological methyl donor, precursor for polyamines and GSH (1). About 50% of methionine metabolism and up to 85% of all methylation reactions occur in the liver (2). 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. Whereas 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, in the adult liver (2). MAT2A is up-regulated during rapid liver growth and dedifferentiation (2). Due to differences in the regulatory and kinetic properties of the various MATs, MAT II cannot maintain the same high levels of SAMe as compared with the combination of MAT I and MAT III (2). Consequently, in MAT1A knockout mice, despite a significant increase in MAT2A expression, the liver content of SAMe is reduced about threefold from birth, when the switch from MAT2A and MAT1A normally takes place (3).It has long been re...

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

“…However, the level of Spred expression was inversely correlated with clinicopathological features, such as metastasis and invasion, which reflect dedifferentiated tumors. Although the mechanism of dedifferentiation of HCC remains to be elucidated, Raf-1 plays a main role in the differentiation of a hepatoblast to a mature hepatocyte (Mikula et al, 2001;Chen et al, 2004). These findings suggest that the reduction of Spred expression may promote the dedifferentiation of HCC through deregulation of the Ras/Raf-1/ERK pathway.…”

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

“…To the best of our knowledge, however, there are no reports that this polymorphism has shown functional effect on the protein or has been associated with any clinical manifestations. Intriguingly, three polymorphisms commonly associated with clinical manifestations, MTHFR (p.V222A/c.677C4T and p.E429A/c.1298A4G) ( Table 1), and CTH (p.I403S/ c.1352G4t), 89 were ranked as low as 27, 23 and 36 out of 38, respectively.…”

“…A MAT1A-null mouse model has also been characterized. 89 This knockout has impaired liver regeneration and spontaneous hepatocellular carcinoma. The localization of these events is likely to be due to the high expression levels of MAT1A in hepatic tissue.…”

“…The localization of these events is likely to be due to the high expression levels of MAT1A in hepatic tissue. 89 Knockout mice null for the FOLR1 homolog, Folbp1, 90 led to embryonic lethality, which could be reversed in heterozygote dams with folinic acid supplementation.…”

“…Knockout mouse pathogenesis CBS [137][138][139][140] Hyperhomocysteinemia Hyperkeratosis MAT1A 89 Spontaneous hepatocellular carcinoma and impaired liver regeneration MTHFR 85,141 Hyperhomocysteinemia (À/+ and À/À) Developmental retardation with cerebellar pathology (À/À) Aortic lipid deposition (À/+ and À/À) Abnormal spermatogenesis (À/À) FOLR1 (Folbp1 Embryonic lethality (À/À) mouse homolog) 90 reversed by folinic acid supplementation of (À/+) dams…”