Gene Expression and DNA Methylation Alterations in the Glycine N-Methyltransferase Gene in Diet-Induced Nonalcoholic Fatty Liver Disease-Associated Carcinogenesis

Journal Article · 14 May 2019 · Toxicological Sciences

DOI: https://doi.org/10.1093/toxsci/kfz110 · OSTI ID:1565976

Borowa-Mazgaj, Barbara ^[1]; de Conti, Aline ^[1]; Tryndyak, Volodymyr ^[1]; Steward, Colleen R. ^[2]; Jimenez, Leandro ^[1]; Melnyk, Stepan ^[3]; Seneshaw, Mulugeta ^[4]; Mirshahi, Faridodin ^[4]; Rusyn, Ivan ^[5]; Beland, Frederick A. ^[1]; Sanyal, Arun J. ^[4]; Pogribny, Igor P. ^[1]

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1. Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079
2. Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, State University of New York at Geneseo, Geneseo, New York 14454
3. Core Metabolomics Laboratory, Arkansas Children’s Research Institute, Little Rock, Arkansas 72202
4. Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia 23298
5. Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843

Abstract Nonalcoholic fatty liver disease (NAFLD) is becoming a major etiological risk factor for hepatocellular carcinoma (HCC) in the United States and other Western countries. In this study, we investigated the role of gene-specific promoter cytosine DNA methylation and gene expression alterations in the development of NAFLD-associated HCC in mice using (1) a diet-induced animal model of NAFLD, (2) a Stelic Animal Model of nonalcoholic steatohepatitis-derived HCC, and (3) a choline- and folate-deficient (CFD) diet (CFD model). We found that the development of NAFLD and its progression to HCC was characterized by down-regulation of glycine N-methyltransferase (Gnmt) and this was mediated by progressive Gnmt promoter cytosine DNA hypermethylation. Using a panel of genetically diverse inbred mice, we observed that Gnmt down-regulation was an early event in the pathogenesis of NAFLD and correlated with the extent of the NAFLD-like liver injury. Reduced GNMT expression was also found in human HCC tissue and liver cancer cell lines. In in vitro experiments, we demonstrated that one of the consequences of GNMT inhibition was an increase in genome methylation facilitated by an elevated level of S-adenosyl-L-methionine. Overall, our findings suggest that reduced Gnmt expression caused by promoter hypermethylation is one of the key molecular events in the development of NAFLD-derived HCC and that assessing Gnmt methylation level may be useful for disease stratification.

• Sponsoring Organization: USDOE
• OSTI ID: 1565976
• Journal Information: Toxicological Sciences, Journal Name: Toxicological Sciences Journal Issue: 2 Vol. 170; ISSN 1096-6080
• Publisher: Oxford University PressCopyright Statement
• Country of Publication: United States
• Language: English