Status of hepatic DNA methylome predetermines and modulates the severity of non-alcoholic fatty liver injury in mice

Abstract

BackgroundNonalcoholic 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.ResultsIn 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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2617-2) contains supplementary material, which is available to authorized users.

Endocrine-disrupting chemicals and fatty liver disease

“…Interestingly, individual mouse strains exhibit differential susceptibility to MDD-induced liver disease, and this difference might be due to inter-strain epigenetic differences. For example, in the WSB/EiJ strain that exhibits severe NASH-like liver injury compared to the A/J strain that exhibits mild NAFLD-like liver injury in response to MDD 135, 136 , increased DNA methylation at gene promoters and increased Dnmt1 and Dnmt3a expression 136 have been reported in the more susceptible strain, consistent with the hypothesis that epigenetic alterations might have a role in modulating NAFLD susceptibility.…”

High fat diet and exercise lead to a disrupted and pathogenic DNA methylome in mouse liver

“…5,6 Novel links between DNA methylation and diet-induced NAFLD have been reported, suggesting that differential DNA methylation is associated with NAFLD development and severity across individuals in animal studies. 7,8 The epigenomic consequences of diet and exercise in liver, where major complications of diet-induced obesity occur, have not been thoroughly investigated. Major questions, including the role of 5-methylcytosine (5mC) in the etiology of NAFLD, whether and how epigenetic reprogramming contributes to disease progression and carcinogenesis, and whether pathologic epigenetic changes can be prevented and reversed are largely unknown.…”

Profiling DNA methylation differences between inbred mouse strains on the Illumina Human Infinium MethylationEPIC microarray

“…DNA methylation can vary substantially between mouse strains and a large fraction of this is likely due to underlying sequence differences between strains [ 21 , 51 , 52 ]. Strain variation in methylation has been shown to associate with complex phenotypes in mice such as insulin resistance, adiposity, and blood cell counts [ 53 ].…”