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. 2022 Feb 11;23(4):1986.
doi: 10.3390/ijms23041986.

Dysregulation of S-adenosylmethionine Metabolism in Nonalcoholic Steatohepatitis Leads to Polyamine Flux and Oxidative Stress

Connor Quinn  1 , Mario C Rico  1 , Carmen Merali  1 , Salim Merali  1
Affiliations

Dysregulation of S-adenosylmethionine Metabolism in Nonalcoholic Steatohepatitis Leads to Polyamine Flux and Oxidative Stress

Connor Quinn et al. Int J Mol Sci. .

Abstract

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.

Keywords: S-adenosylmethionine; glycine-N-methyl transferase; nonalcoholic steatohepatitis; polyamines.

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Conflict of interest statement

Merali consults and has received a grant from TamuroBio. TamuroBio had no influence or input on this publication.

Figures

Figure 1
Figure 1
GNMT is downregulated in human NASH liver. (A) Table displaying patient characteristics for healthy and NASH liver samples. (B) Representative chromatograms from selected reaction monitoring analysis. (C) GNMT protein abundance in human liver samples. Data presented as mean ± SEM (N = 5, * p < 0.05).
Figure 2
Figure 2
Modified amylin diet induces NASH in mice. (A) H&E, Masson trichrome, and Sirius red liver histology staining. Scale bar = 75 µm. (B) Body weight of mice. (C) Results from glucose tolerance test and area under the curve quantitation. (D) The NAS scoring system was used to assess liver histology. Mice fed a modified amylin diet were diagnosed with NASH with a total average NAS score of 6 and fibrosis score of 2. Data presented as mean ± SEM. (N = 7, **** p < 0.0001).
Figure 3
Figure 3
Proteomic characterization of NASH animal model shows human pathophysiology. (A) Heat map displaying differentially regulated proteins involved in apoptosis, lipid metabolism, fibrosis, and inflammation. (B) Individual bar graphs for markers of NASH. Glycine N-methyltransferase (GNMT), platelet glycoprotein 4 (CD36), acyl-coenzyme A thioesterase 9 (Acot9), collagen type 1 alpha 1 chain (COL1A1), actin alpha 2 (Acta2), decorin (Dcn), galectin-3 (Lgals3), interferon-induced protein with tetratricopeptide repeats 3 (Ifit3).
Figure 4
Figure 4
Ingenuity pathway analysis predicts activation of steatohepatitis. (A) Top altered canonical pathways in NASH liver. (B) Steatohepatitis network of differentially expressed proteins contributing to the disease state. Individual proteins are listed in the table below.
Figure 5
Figure 5
Dysregulation of AdoMet metabolism in NASH. (A) Relative protein abundance of select AdoMet regulating enzymes in control and NASH livers. (B) Levels of liver AdoMet and AdoHcy in control and NASH mice. Data presented as mean ± SEM (N = 4, **** p < 0.0001, *** p < 0.001, ** p < 0.01, * p < 0.05).
Figure 6
Figure 6
Polyamine metabolism is activated in NASH causing a flux. (A) Relative protein abundance of select polyamine metabolic enzymes in control and NASH livers. (B) Quantification of polyamine metabolites in control and NASH livers. Data presented as mean ± SEM (N = 4, ** p < 0.01, * p < 0.05).
Figure 7
Figure 7
Increased activity of polyamine oxidase and oxidative damage in NASH. (A) Activity of polyamine oxidase in control and NASH livers. (B) Immunofluorescence staining of control and NASH livers for 4-hydroxynonenal modified proteins. Quantification of the fluorescence is shown on the right. Data presented as mean ± SEM (N = 4, **** p < 0.0001, *** p < 0.001).
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