Dysregulated transmethylation leading to hepatocellular carcinoma compromises redox homeostasis and glucose formation

Curtis C. Hughey, Freyja D. James, Zhizhang Wang, Mickael Goelzer, David H. Wasserman

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: The loss of liver glycine N-methyltransferase (GNMT) promotes liver steatosis and the transition to hepatocellular carcinoma (HCC). Previous work showed endogenous glucose production is reduced in GNMT-null mice with gluconeogenic precursors being used in alternative biosynthetic pathways that utilize methyl donors and are linked to tumorigenesis. This metabolic programming occurs before the appearance of HCC in GNMT-null mice. The metabolic physiology that sustains liver tumor formation in GNMT-null mice is unknown. The studies presented here tested the hypothesis that nutrient flux pivots from glucose production to pathways that incorporate and metabolize methyl groups in GNMT-null mice with HCC. Methods: 2 H/ 13 C metabolic flux analysis was performed in conscious, unrestrained mice lacking GNMT to quantify glucose formation and associated nutrient fluxes. Molecular analyses of livers from mice lacking GNMT including metabolomic, immunoblotting, and immunochemistry were completed to fully interpret the nutrient fluxes. Results: GNMT knockout (KO) mice showed lower blood glucose that was accompanied by a reduction in liver glycogenolysis and gluconeogenesis. NAD + was lower and the NAD(P)H-to-NAD(P) + ratio was higher in livers of KO mice. Indices of NAD + synthesis and catabolism, pentose phosphate pathway flux, and glutathione synthesis were dysregulated in KO mice. Conclusion: Glucose precursor flux away from glucose formation towards pathways that regulate redox status increase in the liver. Moreover, synthesis and scavenging of NAD + are both impaired resulting in reduced concentrations. This metabolic program blunts an increase in methyl donor availability, however, biosynthetic pathways underlying HCC are activated.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalMolecular Metabolism
Volume23
DOIs
StatePublished - May 2019
Externally publishedYes

Bibliographical note

Funding Information:
The authors acknowledge the technical expertise of the Mouse Metabolic Phenotyping Center Analytical Core Services at Vanderbilt University. The Vanderbilt University Medical Center Digital Histology Shared Resource completed the whole slide imaging. This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grants DK050277 and DK054902 (DHW) and Diabetes Canada Postdoctoral Fellowship (CCH). The Mouse Metabolic Phenotyping Center Analytical Core Services are supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK059637 and DK020593 .

Funding Information:
The authors acknowledge the technical expertise of the Mouse Metabolic Phenotyping Center Analytical Core Services at Vanderbilt University. The Vanderbilt University Medical Center Digital Histology Shared Resource completed the whole slide imaging. This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grants DK050277 and DK054902 (DHW) and Diabetes Canada Postdoctoral Fellowship (CCH). The Mouse Metabolic Phenotyping Center Analytical Core Services are supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK059637 and DK020593.

Publisher Copyright:
© 2019 The Authors

Keywords

  • Intermediary metabolism
  • Metabolic flux analysis
  • NAD
  • Redox state
  • S-adenosylmethionine

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