DNA methylation and hepatocarcinogenesis in rats fed a choline-devoid diet

Abstract

Groups of male Fischer-344 rats were fed either a choline-supplemented or a choline-devoid (CD) diet, for up to 14 months. In rats fed the CD diet, hepatic lesions developed and progressed through two distinct stages, the first characterized by severe steatosis and an increase in cell turnover and the second by gradual clearance of the deposited fat, fibrosis and parenchymal nodularity. Large hepatocellular carcinomas were found in rats killed at 14 months. DNA was purified from the livers of all groups of rats and from the tumors, and its level of methylation was analyzed using the restriction endonucleases HpaII and MspI. DNA undermethylation was detected only in the livers of rats fed the CD diet for 14 months, whether bearing tumors or not, and in three of four hepatocellular carcinomas. Undermethylation of liver total DNA is therefore a late effect of dietary choline deficiency in the rat.

Choline: Critical Role During Fetal Development and Dietary Requirements in Adults

“…Dietary choline deficiency not only depletes choline and choline metabolites in rats, but also decreases S-adenosylmethionine concentrations (117,164), with resulting hypomethylation of DNA (74,134). DNA methylation occurs at cytosine bases that are followed by a guanosine (CpG sites) (52) and influences many cellular events, including gene transcription, genomic imprinting, and genomic stability (60,64,105).…”

Phosphatidylcholine functional foods and nutraceuticals: A potential approach to prevent non‐alcoholic fatty liver disease

“…During choline deficiency, hepatic SAM concentrations are decreased by as much as 50% [45][46][47][48]. Animals fed diets deficient in methyl donors (choline and methionine) have hypomethylated DNA [49][50][51]. These deficiencies have been shown to cause both global [52] and gene-specific hypomethylation [53].…”

1,2‐sn‐Diacylglycerol accumulates in choline‐deficient liver

“…Many studies have demonstrated that feeding a choline-devoid diet to experimental animals is carcinogenic [20][21][22][23][24][25][26][27][28][29][30]. There are several mechanisms which have been suggested to explain this effect: increased cell death, increased cell proliferation, decreased DNA methylation, and increased lipid peroxidation.…”

“…Methylation of DNA is important for the regulation of gene expression [34]. It has been suggested that the under-methylation of DNA (decreased 5-methylcytosine content in nuclear DNA), observed during choline deficiency, is responsible for carcinogenesis [26]. Another proposed mechanism is based upon the observation of increased lipid peroxidation in hepatic nuclei isolated from CD animals [35].…”