Maternal obesity predisposes offspring to the development of fatty liver and nonalcoholic steatohepatitis. Using a well-established mouse model (C57BL6/J) of maternal high-fat, high sucrose diet (HFD) exposure, we characterized epigenomic alterations in adult offspring liver. ChiP-seq for six histone modifications were performed on offspring livers from dams fed either a AIN93G (CON, 7% fat calories, n=11) or HFD (45% fat calories, n=9) for 12 wk prior to pregnancy and through weaning. Offspring of HFD dams, showed a robust gain in repressive H3K27me3 modification mediated by the histone methyltransferase, Ezh2. Since Ezh2 has been implicated in modulating inflammatory signaling we examined if Ezh2 in macrophages contributes to hepatic inflammation following a high-fat palmitate/cholesterol (FPC) diet. We generated myeloid cell-specific Ezh2-knockouts (Ezh2-CKO) by crossing Ezh2-floxed (Ezh2f/f) mice to LysM-Cre expressing mice. At 5 weeks of age Ezh2-CKO and flox-control litter mates were provided ad libitum CON (n=22) or FPC diet (52% fat calories, n=22) for 14 days. At 7 weeks of age, body and liver weights were collected and liver tissue was flash frozen for RNA-seq analyses. Two-way ANOVA of liver to body weight ratios showed a significant diet effect (p<0.0001) , with increased ratios in the FPC group without effects of genotype. Transcriptomic analyses showed that the effects of FPC diet were diminished in CKO mice relative to flox controls (223 vs.132 DEGs in flox and CKO, respectively) with 2DEGs shared between genotypes. Ingenuity Pathway Analysis revealed signaling pathways and processes related to inflammation, macrophage and leukocyte activation, reactive oxygen species, and PPARα that were increased in the flox with FPC diets compared to CKO animals. Collectively, these findings reveal a role for Ezh2 in developmental programing of liver disease and hepatic inflammation, uncovering a novel epigenetic process influencing hepatic disease risk in offspring.

Disclosure

M.L.Ruebel: None. P.Jambal: None. S.V.Chintapalli: None. J.Chen: None. K.Shankar: None.

Funding

U.S. Department of Agriculture-ARS-CRIS (6251-51000-005-00D) NIH (P30DK048520-27, R01HD102726-01A1) Funds from the Department of Pediatrics, University of ColoradoAnschutz Medical Campus and the Anschutz Health and Wellness Center.

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