Glycine N-methyltransferase deletion in mice diverts carbon flux from gluconeogenesis to pathways that utilize excess methionine cycle intermediates

Abstract

Glycine -methyltransferase (GNMT) is the most abundant liver methyltransferase regulating the availability of the biological methyl donor,-adenosylmethionine (SAM). Moreover, GNMT has been identified to be down-regulated in hepatocellular carcinoma (HCC). Despite its role in regulating SAM levels and association of its down-regulation with liver tumorigenesis, the impact of reduced GNMT on metabolic reprogramming before the manifestation of HCC has not been investigated in detail. Herein, we used H/C metabolic flux analysis in conscious, unrestrained mice to test the hypothesis that the absence of GNMT causes metabolic reprogramming. GNMT-null (KO) mice displayed a reduction in blood glucose that was associated with a decline in both hepatic glycogenolysis and gluconeogenesis. The reduced gluconeogenesis was due to a decrease in liver gluconeogenic precursors, citric acid cycle fluxes, and anaplerosis and cataplerosis. A concurrent elevation in both hepatic SAM and metabolites of SAM utilization pathways was observed in the KO mice. Specifically, the increase in metabolites of SAM utilization pathways indicated that hepatic polyamine synthesis and catabolism, transsulfuration, and lipogenesis pathways were increased in the KO mice. Of note, these pathways utilize substrates that could otherwise be used for gluconeogenesis. Also, this metabolic reprogramming occurs before the well-documented appearance of HCC in GNMT-null mice. Together, these results indicate that GNMT deletion promotes a metabolic shift whereby nutrients are channeled away from glucose formation toward pathways that utilize the elevated SAM.

Targeted and untargeted metabolomics provide insight into the consequences of glycine‐N‐methyltransferase deficiency including the novel finding of defective immune function

“…(Bello & Liang, 2011). In addition, there has been recent evidence that GNMT -/mice have enhanced flux through some methylation reactions in the liver (Hughey et al, 2018) and this is supported by our current findings. This hypermethylation phenotype in GNMT -/mice could enhance catechol-O-methyltransferase activity in the brain and thereby interfere with catecholamine signaling.…”

Construction and Validation of a Metabolic Reprogramming Related Prognostic Model for Hepatocellular Carcinoma

“…Enhanced glycolysis in hepatocellular carcinoma can be explained as metabolic adaptation to the tumor microenvironment. In addition, our ndings were consistent with those of Curtis C, et al [27], in which glycosoplasmas were transferred to regulate oxidative stress and countered SAM elevation, thereby regulating hepatocellular carcinoma biosynthetic pathways.…”

The complexity of the serine glycine one-carbon pathway in cancer

“…For example, loss of glycine N-methyltransferase in the liver promotes SAM accumulation, which is associated with hepatomegaly and precedes HCC. While the causality has not yet been fully established, SAM accumulation in this context correlates with increased lipogenesis, polyamine biosynthesis, and transulfuration activity (Hughey et al, 2018). All of these reactions might account for the increased anabolic activity required for tumorigenesis.…”