Impaired liver regeneration in mice lacking glycine N-methyltransferase

Marta Varela-Rey, David Fernández-Ramos, Nuria Martínez-López, Nieves Embade, Laura Gómez-Santos, Naiara Beraza, Mercedes Vázquez-Chantada, Juan Rodríguez, Zigmund Luka, Conrad Wagner, Shelly C. Lu, M. Luz Martínez-Chantar, José M. Mato

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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 κB(NFκB), 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. NFκB, 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 NFκB 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.

Original languageEnglish (US)
Pages (from-to)443-452
Number of pages10
JournalHepatology
Volume50
Issue number2
DOIs
Publication statusPublished - Nov 26 2009

    Fingerprint

ASJC Scopus subject areas

  • Hepatology

Cite this

Varela-Rey, M., Fernández-Ramos, D., Martínez-López, N., Embade, N., Gómez-Santos, L., Beraza, N., ... Mato, J. M. (2009). Impaired liver regeneration in mice lacking glycine N-methyltransferase. Hepatology, 50(2), 443-452. https://doi.org/10.1002/hep.23033