Nonalcoholic fatty liver disease (
NAFLD) is the number one cause of chronic
liver disease worldwide, with 25% of these patients developing
nonalcoholic steatohepatitis (NASH). NASH significantly increases the risk of
cirrhosis and decompensated
liver failure. Past studies in rodent models have shown that
glycine-N-methyltransferase (GNMT) knockout results in rapid steatosis,
fibrosis, and
hepatocellular carcinoma progression. However, the attenuation of GNMT in subjects with NASH and the molecular basis for its impact on the disease process is still unclear. To address this knowledge gap, we show the reduction of GNMT
protein levels in the liver of NASH subjects compared to healthy controls. To gain insight into the impact of decreased GNMT in the disease process, we performed global label-free
proteome studies on the livers from a murine modified
amylin diet-based model of NASH. Histological and molecular characterization of the animal model demonstrate a high resemblance to human disease. We found that a reduction of GNMT leads to a significant increase in
S-adenosylmethionine (
AdoMet), an essential metabolite for transmethylation reactions and a substrate for
polyamine synthesis. Further targeted proteomic and metabolomic studies demonstrated a decrease in GNMT transmethylation, increased flux through the
polyamine pathway, and increased oxidative stress production contributing to NASH pathogenesis.