Unknown,Transcriptomics,Genomics,Proteomics

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Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and developed countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD. The goals of this study were to compare the magnitude of interindividual differences in the severity of liver injury induced by methyl-donor deficiency among individual inbred strains of mice and to investigate the underlying mechanisms associated with the variability. Feeding mice a choline- and folate-deficient diet for 12 wk caused liver injury similar to NAFLD. The magnitude of liver injury varied among the strains, with the order of sensitivity being A/J M-bM-^IM-^H C57BL/6J M-bM-^IM-^H C3H/HeJ < 129S1/SvImJ M-bM-^IM-^H CAST/EiJ < PWK/PhJ < WSB/EiJ. The interstrain variability in severity of NAFLD liver damage was associated with dysregulation of genes involved in lipid metabolism, primarily with a down-regulation of the peroxisome proliferator receptor M-NM-1 (PPARM-NM-1)-regulated lipid catabolic pathway genes. Markers of oxidative stress and oxidative stress-induced DNA damage were also elevated in the livers but were not correlated with severity of liver damage. These findings suggest that the PPARM-NM-1-regulated metabolism network is one of the key mechanisms determining interstrain susceptibility and severity of NAFLD in mice. Male A/J, C3H/HeJ and WSB/EiJ inbred mice were maintained on either control or choline- and folate-deficient (CFD) diets for 12 weeks. Gene expression profiles in the livers from control mice and mice fed a CFD-diet were investigated.

ORGANISM(S): Mus musculus

SUBMITTER: Volodymyr Tryndyak

PROVIDER: E-GEOD-62362 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism.

Tryndyak Volodymyr V de Conti Aline A Kobets Tetyana T Kutanzi Kristy K Koturbash Igor I Han Tao T Fuscoe James C JC Latendresse John R JR Melnyk Stepan S Shymonyak Svitlana S Collins Leonard L Ross Sharon A SA Rusyn Ivan I Beland Frederick A FA Pogribny Igor P IP

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20120807 11

Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and developed countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD. The goals of this study were to compare the magnitude of interindividual differences in the severity of liver injury induced by methyl-donor deficiency among individual inbred strains of mice and to investigate the underlying mechanisms associated with the vari ...[more]

PMID: 22872676

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Project description:Tamoxifen is a non-steroidal anti-estrogenic drug widely used for the treatment and prevention of breast cancer in women; however, there is evidence that tamoxifen is hepatocarcinogenic in rats, but not in mice. Additionally, it has been reported that tamoxifen may cause non-alcoholic fatty liver disease (NAFLD) in humans and experimental animals. The goals of the present study were to (i) investigate the mechanisms of the resistance of mice to tamoxifen-induced hepatocarcinogenesis, and (ii) clarify effects of tamoxifen on NAFLD-associated liver injury. Feeding female WSB/EiJ mice a 420 p.p.m. tamoxifen-containing diet for 12 weeks resulted in an accumulation of tamoxifen-DNA adducts, (E)-M-NM-1-(deoxyguanosin-N2-yl)-tamoxifen (dG-TAM) and (E)-M-NM-1-(deoxyguanosin-N2-yl)-N-desmethyltamoxifen (dG-DesMeTAM), in the livers. The levels of hepatic dG-TAM and dG-DesMeTAM DNA adducts in tamoxifen-treated mice were 578 and 340 adducts/108 nucleotides, respectively, while the extent of global DNA and repetitive elements methylation and histone modifications did not differ from the values in control mice. Additionally, there was no biochemical or histopathological evidence of NAFLD-associated liver injury in mice treated with tamoxifen. A transcriptomic analysis of differentially expressed genes demonstrated that tamoxifen caused predominantly down-regulation of hepatic lipid metabolism genes accompanied by a distinct over-expression of the lipocalin 13 (Lcn13) and peroxisome proliferator receptor gamma (PparM-NM-3), which may prevent the development of NAFLD. The results of the present study demonstrate that the resistance of mice to tamoxifen-induced liver carcinogenesis may be associated with its ability to induce genotoxic alterations only without affecting the cellular epigenome and an inability of tamoxifen to induce the development of NAFLD. Female and male WSB/EiJ mice were fed diet containing 420 p.p.m. tamoxifen for 12 weeks, and then tamoxifen-DNA adduct formation and gene expression profiles in the livers from four control and four tamoxifen-treated mice were investigated.

Dataset Information

Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism.

Publications

Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism.

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