Status of hepatic DNA methylome predetermines and modulates the severity of non-alcoholic fatty liver injury in mice.
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and Western countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD; nonetheless, the effect of inter-individual differences in the normal liver epigenome with regard to the susceptibility to NAFLD has not been determined.


RESULTS
In the present study, we investigated the association between the DNA methylation status in the livers of A/J and WSB/EiJ mice and the severity of NAFLD-associated liver injury. We demonstrate that A/J and WSB/EiJ mice, which are characterized by significant differences in the severity of liver injury induced by a choline- and folate-deficient (CFD) diet exhibit substantial differences in cytosine DNA methylation in their normal livers. Furthermore, feeding A/J and WSB/EiJ mice a CFD diet for 12 weeks resulted in different trends and changes in hepatic cytosine DNA methylation.


CONCLUSIONS
Our findings indicate a primary role of hepatic DNA methylation in the pathogenesis of NAFLD and suggest that individual variations in DNA methylation across the genome may be a factor determining and influencing the vulnerability to NAFLD.
Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, 3900 NCTR Rd, Jefferson, AR, 72079, USA.
Volodymyr P
VP
Tryndyak
Division of Systems Biology, National Center for Toxicological Research, FDA, Jefferson, AR, USA.
Tao
T
Han
Division of Systems Biology, National Center for Toxicological Research, FDA, Jefferson, AR, USA.
James C
JC
Fuscoe
Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.
Sharon A
SA
Ross
Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, 3900 NCTR Rd, Jefferson, AR, 72079, USA.
Frederick A
FA
Beland
Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, 3900 NCTR Rd, Jefferson, AR, 72079, USA. igor.pogribny@fda.hhs.gov.
Igor P
IP
Pogribny
D000818:Animals; D002794:Choline; D018899:CpG Islands; D003596:Cytosine / Q000737:chemistry; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004032:Diet; D044127:Epigenesis, Genetic; D005492:Folic Acid; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000503:physiopathology*; D051379:Mice; D008805:Mice, Inbred A; D008815:Mice, Inbred Strains; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics*
C000717967:DNMT3A protein, human; D006657:Histones; D003596:Cytosine; D005492:Folic Acid; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D002794:Choline
DNA methylation; Inter-strain differences; Mouse; Non-alcoholic fatty liver injury; Susceptibility