Impaired liver regeneration in mice lacking glycine N-methyltransferase

Hepatology. 2009 Aug;50(2):443-52. doi: 10.1002/hep.23033.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • NF-kappa B
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • S-Adenosylmethionine
  • Nitric Oxide Synthase Type III
  • Glycine N-Methyltransferase
  • Gnmt protein, mouse
  • Protein Serine-Threonine Kinases
  • Stk11 protein, mouse
  • AMP-Activated Protein Kinases