Impaired liver regeneration in mice lacking glycine N-methyltransferase.

Varela-Rey M, Fernández-Ramos D, Martínez-López N, Embade N, Gómez-Santos L, Beraza N, Vázquez-Chantada M, Rodríguez J, Luka Z, Wagner C, Lu SC, Martínez-Chantar ML, Mato JM
Hepatology. 2009 50 (2): 443-52

PMID: 19582817 · PMCID: PMC2805126 · DOI:10.1002/hep.23033

UNLABELLED - Hepatic S-adenosylmethionine (SAMe) is maintained constant by the action of methionine adenosyltransferase I/III (MATI/III), which converts methionine into SAMe and glycine N-methyltransferase (GNMT), which eliminates excess SAMe to avoid aberrant methylation reactions. During liver regeneration after partial hepatectomy (PH) MATI/III activity is inhibited leading to a decrease in SAMe. This injury-related reduction in SAMe promotes hepatocyte proliferation because SAMe inhibits hepatocyte DNA synthesis. In MATI/III-deficient mice, hepatic SAMe is reduced, resulting in uncontrolled hepatocyte growth and impaired liver regeneration. These observations suggest that a reduction in SAMe is crucial for successful liver regeneration. In support of this hypothesis we report that liver regeneration is impaired in GNMT knockout (GNMT-KO) mice. Liver SAMe is 50-fold higher in GNMT-KO mice than in control animals and is maintained constant following PH. Mortality after PH was higher in GNMT-KO mice than in control animals. In GNMT-KO mice, nuclear factor kappaB (NFkappaB), signal transducer and activator of transcription-3 (STAT3), inducible nitric oxide synthase (iNOS), cyclin D1, cyclin A, and poly (ADP-ribose) polymerase were activated at baseline. PH in GNMT-KO mice was followed by the inactivation of STAT3 phosphorylation and iNOS expression. NFkappaB, cyclin D1 and cyclin A were not further activated after PH. The LKB1/AMP-activated protein kinase/endothelial nitric oxide synthase cascade was inhibited, and cytoplasmic HuR translocation was blocked despite preserved induction of DNA synthesis in GNMT-KO after PH. Furthermore, a previously unexpected relationship between AMPK phosphorylation and NFkappaB activation was uncovered.

CONCLUSION - These results indicate that multiple signaling pathways are impaired during the liver regenerative response in GNMT-KO mice, suggesting that GNMT plays a critical role during liver regeneration, promoting hepatocyte viability and normal proliferation.

MeSH Terms (18)

AMP-Activated Protein Kinases Animals Cell Cycle Cells, Cultured Glycine N-Methyltransferase Hepatectomy Hepatocytes Liver Regeneration Male Mice Mice, Knockout NF-kappa B Nitric Oxide Synthase Type III Phosphorylation Protein-Serine-Threonine Kinases S-Adenosylmethionine Signal Transduction STAT3 Transcription Factor

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