Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A.
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 kappaB (NFkappaB), 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 NFkappaB and STAT-3 are similar to wild-type mice. Following PH, early activation of these pathways occurred, but although they remained increased in wild-type 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.
Chen
Lixin
L
Division of Gastroenterology and Liver Diseases, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, USC Liver Disease Research Center, USC School of Medicine, Los Angeles, California 90033, USA.
Zeng
Ying
Y
Yang
Heping
H
Lee
Taunia D
TD
French
Samuel W
SW
Corrales
Fernando J
FJ
García-Trevijano
Elena R
ER
Avila
Matías A
MA
Mato
José M
JM
Lu
Shelly C
SC
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D019938:Cyclin D1 / Q000502:physiology; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000502:physiology; D020869:Gene Expression Profiling; D006498:Hepatectomy / Q000379:methods; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000201:enzymology* / Q000378:metabolism; D015850:Interleukin-6 / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D008716:Methionine Adenosyltransferase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008938:Mitosis / Q000187:drug effects; D016328:NF-kappa B / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D009928:Organ Specificity; D012333:RNA, Messenger / Q000096:biosynthesis; D012436:S-Adenosylmethionine / Q000172:deficiency / Q000502:physiology*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; D009569:Nitric Oxide; D017228:Hepatocyte Growth Factor; D012436:S-Adenosylmethionine; D000255:Adenosine Triphosphate; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases