Dietary Methyl Deficiency, microRNA Expression and Susceptibility to Liver Carcinogenesis

Starlard‐Davenport, Athena; Tryndyak, Volodymyr; Kosyk, Oksana; Ross, Sharon R.; Rusyn, Ivan; Beland, Frederick A.; Pogribny, Igor P.

doi:10.1159/000324362

Cited by 10 publications

(11 citation statements)

References 49 publications

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“…Aberrant expression of miRNAs, driven by both genetic and epigenetic factors and involved in cancer initiation and progression, has been shown to be reversed by various dietary components (Davis and Ross, 2008; Saini et al ., 2010; Parasramka et al ., 2012). A recent study by Starlard‐Davenport et al . (2010) demonstrated alterations in the expression of miRNAs, induced by methyl deficiency, as a prominent event during the early stages of liver carcinogenesis and suggests that the pattern of miRNAs expression may predict susceptibility to liver carcinogenesis.…”

Section: The Impact Of Natural Compounds On the Regulation Of Mirnasmentioning

confidence: 97%

Epigenetic mechanisms in anti‐cancer actions of bioactive food components – the implications in cancer prevention

Stefańska

Karlic

Varga

et al. 2012

British J Pharmacology

168

108

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The hallmarks of carcinogenesis are aberrations in gene expression and protein function caused by both genetic and epigenetic modifications. Epigenetics refers to the changes in gene expression programming that alter the phenotype in the absence of a change in DNA sequence. Epigenetic modifications, which include amongst others DNA methylation, covalent modifications of histone tails and regulation by non-coding RNAs, play a significant role in normal development and genome stability. The changes are dynamic and serve as an adaptation mechanism to a wide variety of environmental and social factors including diet. A number of studies have provided evidence that some natural bioactive compounds found in food and herbs can modulate gene expression by targeting different elements of the epigenetic machinery. Nutrients that are components of one-carbon metabolism, such as folate, riboflavin, pyridoxine, cobalamin, choline, betaine and methionine, affect DNA methylation by regulating the levels of S-adenosyl-L-methionine, a methyl group donor, and S-adenosyl-Lhomocysteine, which is an inhibitor of enzymes catalyzing the DNA methylation reaction. Other natural compounds target histone modifications and levels of non-coding RNAs such as vitamin D, which recruits histone acetylases, or resveratrol, which activates the deacetylase sirtuin and regulates oncogenic and tumour suppressor micro-RNAs. As epigenetic abnormalities have been shown to be both causative and contributing factors in different health conditions including cancer, natural compounds that are direct or indirect regulators of the epigenome constitute an excellent approach in cancer prevention and potentially in anti-cancer therapy. AbbreviationsDNMTs, DNA methyltransferases; EGCG, (-)-epigallocatechin-3-gallate; HATs, histone acetylases; HCC, hepatocellular carcinoma; HDACs, histone deacetylases; MBDs, methyl-CpG-binding domain proteins; miRNAs, micro-RNAs; MTHF, methylenetetrahydrofolate; RA, retinoic acid; RES, resveratrol; SAH, S-adenosyl-L-homocysteine; SAM, S-adenosyl-L-methionine; UHRF1, ubiquitin-like containing PHD ring finger 1; Vit.D3, vitamin D3 IntroductionCancer initiation and progression are driven by the concurrent changes in the expression of multiple genes that occur via genetic and epigenetic alterations, leading to either activation of oncogenes and prometastatic genes, or silencing of tumour suppressor genes and to genome rearrangements and instability (Baylin et al., 2001; Widschwendter and Jones, BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2012 British Journal of Pharmacology (2012) Szyf, 2005;Stefanska et al., 2011a). Epigenetic modifications have attracted a significant amount of attention in the prevention and treatment of different illnesses, with cancer at the forefront, mainly due to their reversibility. Epigenetics refers to layers of information in addition to genetics and comprises several components such as DNA methylation, covalent histone modifications, particularly histone acetylation and me...

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Section: The Impact Of Natural Compounds On the Regulation Of Mirnasmentioning

confidence: 97%

Epigenetic mechanisms in anti‐cancer actions of bioactive food components – the implications in cancer prevention

Stefańska

Karlic

Varga

et al. 2012

British J Pharmacology

168

108

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“…The research of dietary models of NAFLD and development stages in animal models include the assessment of changes by methyl donor group administration on the diet, with depletion of choline and methionine (Rinella et al 2008;Vetelainen et al 2007), or of vitamin B 12 and folic acid (Brunaud et al 2003). These impairments alter the hepatic epigenetic profile and accelerate the progression from slight liver injury to cancer (Pogribny et al 2009;Starlard-Davenport et al 2010). On the contrary, a promethylation cocktail including choline, betaine, folic acid, and vitamin B 12 in a transgenerational model of obesity in agouti mice produced phenotypical and epigenetic alterations, where the agouti transposon was blocked and heritable obesity minimized (Waterland et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet

et al. 2012

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Non-alcoholic fatty liver disease (NAFLD) is one of the first hepatic manifestations of metabolic syndrome, whose progression can lead to cirrhosis and hepatic carcinoma. Interestingly, methyl donor supplementation could improve obesogenic diet-induced hepatic triglyceride accumulation. The aim of this research is to describe methyl donor effects on a high-fat-sucrose (HFS) diet in both sexes and epigenetic changes induced on fatty acid synthase (FASN) promoter methylation pattern as well as gene expression of NAFLD key metabolic genes. Twenty-four male and 28 female Wistar rats were assigned to three dietary groups: control, HFS, and HFS supplemented with methyl donors (choline, betaine, vitamin B12, and folic acid). After 8 weeks of treatment, somatic, biochemical, mRNA, and epigenetic measurements were performed. Rats fed the HFS diet presented an overweight phenotype and alterations in plasma biochemical measurements. Methyl donor supplementation reverted the HFS-diet-induced hepatic triglyceride accumulation. Analysis of FASN promoter cytosine methylation showed changes in both sexes due to the obesogenic diet at -1,096, -780, -778, and -774 CpG sites with respect to the transcriptional start site. Methyl donor supplementation modified DNA methylation at -852, -833, -829, -743, and -733 CpGs depending on the sex. RT-PCR analysis confirmed that FASN expression tended to be altered in males. Our findings reinforce the hypothesis that methyl donor supplementation can prevent hepatic triglyceride accumulation induced by obesogenic diets in both sexes. Changes in liver gene expression profile and epigenetic-mediated mechanisms related to FASN DNA hypermethylation could be involved in methyl donor-induced NAFLD improvement.

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“…24 Furthermore, dietary depletion of these molecules, mainly choline and betaine, has been used to achieve animal models of NAFLD and advanced states of nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma. 25,26 In contrast, dietary supplementation with methyl donors in adult animals protected against obesogenic diet-induced NAFLD. 13,14,16 Therefore, we hypothesized that supplementation of methyl donors in early life would protect against adverse programming effects on metabolic health of the adult offspring due to maternal HFS.…”

Section: Discussionmentioning

confidence: 99%

Supplementation with methyl donors during lactation to high-fat-sucrose-fed dams protects offspring against liver fat accumulation when consuming an obesogenic diet

Cordero

Milagro

Campión

et al. 2014

J Dev Orig Health Dis

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Methyl donor supplementation has been reported to prevent obesity-induced liver fat accumulation in adult rats. We hypothesized that this protection could be mediated by perinatal nutrition. For this purpose, we assessed the response to an obesogenic diet (high-fat-sucrose, HFS) during adulthood depending on maternal diet during lactation. Female Wistar rats fed control diet during pregnancy were assigned to four postpartum dietary groups: control, control supplemented with methyl donors (choline, betaine, folic acid, vitamin B12), HFS and HFS supplemented with methyl donors. At weaning, the male offspring was transferred to a chow diet and at week 12th assigned to a control or a HFS diet during 8 weeks. The offspring whose mothers were fed HFS during lactation showed increased adiposity (19%, P<0.001). When fed the HFS diet as adults, offspring whose mothers were HFS supplemented had more body fat (23%, P<0.001) than those from HFS non-supplemented. However, they showed lower liver fat accumulation (-18%, P<0.001). Srebf1, Dnmt1 and Lepr liver mRNA levels increased after adulthood HFS feeding. In those animals HFS fed during adulthood, previous maternal HFS decreased Lepr and Dnmt1 expression levels when compared with c-HFS offspring, while the supplementation of control and HFS-fed dams, respectively, induced higher hepatic Mme and Lepr mRNA levels after adult HFS intake compared with hfs-HFS offspring. In conclusion, maternal HFS diet during lactation influenced the response to an obesogenic diet in the adult progeny. Interestingly, dietary methyl donor supplementation in lactating mothers fed an obesogenic diet reduced liver fat accumulation, but increased adipose tissue storage in adult HFS-fed offspring.

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Dietary Methyl Deficiency, microRNA Expression and Susceptibility to Liver Carcinogenesis

Cited by 10 publications

References 49 publications

Epigenetic mechanisms in anti‐cancer actions of bioactive food components – the implications in cancer prevention

Epigenetic mechanisms in anti‐cancer actions of bioactive food components – the implications in cancer prevention

Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet

Supplementation with methyl donors during lactation to high-fat-sucrose-fed dams protects offspring against liver fat accumulation when consuming an obesogenic diet

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