Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet☆

Background/Aims

The importance of epigenetic changes in etiology and pathogenesis of disease has been increasingly recognized. However, the role of epigenetic alterations in the genesis of hepatic steatosis and cause of individual susceptibilities to this pathological state are largely unknown.

Methods

Male inbred C57BL/6J and DBA/2J mice were fed a lipogenic methyl-deficient diet (MDD) that causes liver injury similar to human non-alcoholic steatohepatitis (NASH) for 6, 12, or 18 weeks, and the status of global and repetitive elements cytosine methylation, histone modifications, and expression of proteins responsible for those epigenetic modifications in livers was determined.

Results

The development of hepatic steatosis in inbred C57BL/6J and DBA/2J mice was accompanied by prominent epigenetic abnormalities. This was evidenced by pronounced loss of genomic and repetitive sequences cytosine methylation, especially at major and minor satellites, accompanied by increased levels of repeat-associated transcripts, aberrant histone modifications, and alterations in expression of the maintenance DNA methyltransferase 1 (DNMT1) and de novo DNMT3A proteins in the livers of both mouse strains. However, the DBA/2J mice, which were characterized by an initially lower degree of methylation of repetitive elements and lower extent of histone H3 lysine 9 (H3K9) and H3 lysine 27 (H3K27) trimethylation in the normal livers, as compared to those in the C57BL/6J mice, developed more prominent NASH-specific pathomorphological changes.

Conclusions

These results mechanistically link epigenetic alterations to the pathogenesis of hepatic steatosis and strongly suggest that differences in the cellular epigenetic status may be a predetermining factor to individual susceptibilities to hepatic steatosis.

Keywords: Hepatic steatosis, Non-alcoholic steatohepatitis, DNA methylation, Histone modifications, Disease susceptibility

Abbreviations: NASH, non-alcoholic steatohepatitis, MDD, methyl-deficient diet, MAD, methyl-adequate diet, DNMT, DNA methyltransferase, KMT, histone lysine methyltransferase, SAM, S-adenosyl-l-methionine, SAH, S-adenosyl-l-homocysteine, H3K9, histone H3 lysine 9, H3K27, histone H3 lysine 27, H4K20, histone H4 lysine 20, qRT-PCR, quantitative real-time-PCR, IAP, intracesternal A particle, LINE, long interspersed element, SINE, short interspersed element, ANOVA, analysis of variance, LCFA, long-chain fatty acid, Cpt1, carnitine palmitoyltransferase 1, Gapdh, glyceraldehyde-3-phosphate dehydrogenase