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

被引:29
|
作者
Borowa-Mazgaj, Barbara [1 ]
de Conti, Aline [1 ]
Tryndyak, Volodymyr [1 ]
Steward, Colleen R. [1 ,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 ]
机构
[1] Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA
[2] SUNY Coll Geneseo, Geneseo, NY 14454 USA
[3] Arkansas Childrens Res Inst, Core Metabol Lab, Little Rock, AR 72202 USA
[4] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA 23298 USA
[5] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA
关键词
epigenetics; Gnmt; HCC; NASH; NAFLD; HEPATOCELLULAR-CARCINOMA; UNITED-STATES; PLASMA; TRENDS; GNMT; DEFICIENCY; METABOLISM; PROTEIN; MODEL; MICE;
D O I
10.1093/toxsci/kfz110
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
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.
引用
收藏
页码:273 / 282
页数:10
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