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Dysregulated transmethylation leading to hepatocellular carcinoma compromises
redox homeostasis and glucose formation.
Authors Hughey CC, James FD, Wang Z, Goelzer M, Wasserman DH
Submitted By Submitted Externally on 5/13/2019
Status Published
Journal Molecular metabolism
Year 2019
Date Published 5/1/2019
Volume : Pages 23 : 1 - 13
PubMed Reference 30850319
Abstract 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., 2H/13C 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., 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., 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


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