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Disrupted liver oxidative metabolism in glycine N-methyltransferase-deficient
mice is mitigated by dietary methionine restriction.
Authors Rome FI, Hughey CC
Submitted By Submitted Externally on 3/9/2022
Status Published
Journal Molecular metabolism
Year 2022
Date Published 2/1/2022
Volume : Pages 58 : 101452
PubMed Reference 35121169
Abstract One-carbon metabolism is routinely dysregulated in nonalcoholic fatty liver
disease. This includes decreased glycine N-methyltransferase (GNMT), a critical
regulator of s-adenosylmethionine (SAM). Deletion of GNMT in mice increases SAM
and promotes liver steatosis. Lower liver oxidative metabolism, as indicated by
a decline in gluconeogenesis, citric acid cycle flux, and oxidative
phosphorylation contributes to liver steatosis in GNMT-null mice; however, the
extent to which higher SAM mediates this phenotype remains unclear. Here, we
determined the SAM-dependent impairment in liver oxidative metabolism by loss of
GNMT., GNMT knockout (KO) mice were fed a methionine-restricted diet to prevent
increased SAM. 2H/13C metabolic flux analysis was performed in conscious,
unrestrained mice to quantify liver nutrient fluxes. Metabolomics and
high-resolution respirometry were used to quantify liver nutrient pool sizes and
mitochondrial oxidative phosphorylation, respectively. Folic acid-supplemented
and serine/glycine-deficient diets were used independently to further define the
metabolic implications of perturbed one-carbon donor availability., Dietary
methionine restriction prevented a 75-fold increase in SAM and a 53% rise in
triacylglycerides in livers of KO mice. Dietary methionine restriction increased
gluconeogenesis, independent of genotype, and restored cytochrome c oxidase
respiratory function in KO mice. Citric acid cycle fluxes remained lower in KO
mice irrespective of diet. Restricting dietary methionine abrogated markers of
increased lipogenesis and folate cycle dysfunction in KO mice., The impaired
liver oxidative metabolism following loss of GNMT is both dependent and
independent of greater SAM availability. Lower in vivo citric acid cycle flux is
independent of increased SAM. In contrast, gluconeogenesis and oxidative
phosphorylation are negatively regulated by excess SAM. Lipid accumulation in
livers of mice lacking GNMT is also linked to higher SAM.


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