Disrupted liver oxidative metabolism in glycine N-methyltransferase-deficient mice is mitigated by dietary methionine restriction

OBJECTIVE: 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. METHODS: GNMT knockout (KO) mice were fed a methionine-restricted diet to prevent increased SAM. (2)H/(13)C 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. RESULTS: 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. CONCLUSIONS: 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.