430 - Early-life Stress Perturbs the Epigenetics of Cd36 Concurrent with Adult-onset of NAFLD in Mice
Saturday, April 29, 2023
3:30 PM – 6:00 PM ET
Poster Number: 430 Publication Number: 430.219
Qi Fu, Children's Mercy Hospital Kansas City, Kansas City, KS, United States; Jenna Frick, University of Kansas Medical Center, Kansas City, KS, United States; Olivia Eller, University of Kansas Medical Center, Kansas City, KS, United States; John Thyfault, KUMC, Kansas City, KS, United States; Julie A. Christianson, University of Kansas School of Medicine, Kansas City, KS, United States; Robert H. Lane, Children's Mercy, Kansas City, MO, United States
Research Scientist Children's Mercy Hospital Kansas City Kansas City, Missouri, United States
Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the U.S. and worldwide. The influence of early life stress (ELS) on the pathogenesis of NAFLD remains largely unknown and receives relatively little attention. We have previously found that ELS in conjunction with a postweaning high fat-and sucrose- diet (HFS) increased the chances of developing NAFLD in adult mice. And the pathogenic effects correlate with perturbation of the expression and epigenetics of the fatty acid translocase (CD36). But it is unknown if our previous findings are applicable to other types of ELS. Objective: We hypothesized that neonatal maternal separation (NMS), a common early life stress related to modern-life style, together with postweaning HFS diet would increase the chances of developing NAFLD, and increase hepatic CD36 expression, alter its epigenetics, such as methylation of CD36 promoters in a mouse model. Design/Methods: NMS was implemented from birth to weaning with no stress on the controls (Naïve). HFS diet was started since week 4 of life and four experimental group was generated: Naïve-control diet (CD), Naïve-HFS, NMS-CD, and NMS-HFS. Liver phenotypes were characterized at week of 25 of life. Bisulfite pyrosequencing quantified DNA methylation. Results: NMS alone caused NAFLD in adult male mice at 25 weeks of age. The effects of NMS and HFS were generally additive in males in terms of NAFLD, hepatic CD36 mRNA levels, and hepatic CD36 promoter DNA hypomethylation. CD36 promoter methylation significantly negatively correlated with CD36 mRNA levels. Two differentially methylated regions (DMRs) within CD36 promoters 2 and 3 appeared to be vulnerable to NMS in the mice.
Conclusion(s): Hepatic CD36 plays a role in the NMS-related adult-onset NAFLD. The findings in males parallel similar findings from a previous mouse model involving a maternal adverse early-life environment conducted at another institution. Considering the methodological differences between the two models, we speculate that hypomethylation of the hepatic CD36 DMRs represents a conserved mechanism through which adverse early life event and stressors initiate the pathogenesis of later life NAFLD.
