Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet.
OBJECTIVE
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.
Pogribny
Igor P
IP
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA. igor.pogribny@fda.hhs.gov
Tryndyak
Volodymyr P
VP
Bagnyukova
Tetyana V
TV
Melnyk
Stepan
S
Montgomery
Beverly
B
Ross
Sharon A
SA
Latendresse
John R
JR
Rusyn
Ivan
I
Beland
Frederick A
FA
D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D019175:DNA Methylation; D004198:Disease Susceptibility; D044127:Epigenesis, Genetic; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D005494:Folic Acid Deficiency / Q000150:complications; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D013045:Species Specificity
D006657:Histones; D008715:Methionine