Early-life stress perturbs the epigenetics of Cd36 concurrent with adult onset of NAFLD in mice

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the U.S. and worldwide. The roles of early postnatal life stress (EPLS) and the fatty acid translocase (CD36) on the pathogenesis of adult-onset NAFLD remain unknown. We hypothesized that EPLS, in the form of neonatal maternal separation (NMS), would predispose mice towards developing adult NAFLD, increase hepatic CD36 expression, and differentially methylate Cd36 promoter concurrently. METHODS: NMS was performed on mice from postnatal day 1 to 21 and a high-fat/high-sucrose (HFS) diet was started at 4 weeks of age to generate four experimental groups: Naive-control diet (CD), Naive-HFS, NMS-CD, and NMS-HFS. RESULTS: NMS alone caused NAFLD in adult male mice at 25 weeks of age. The effects of NMS and HFS were generally additive in terms of NAFLD, hepatic Cd36 mRNA levels, and hepatic Cd36 promoter DNA hypomethylation. Cd36 promoter methylation negatively correlated with Cd36 mRNA levels. Two differentially methylated regions (DMRs) within Cd36 promoter regions appeared to be vulnerable to NMS in the mouse. CONCLUSIONS: Our findings suggest that NMS increases the risk of an individual, particularly male, towards NAFLD when faced with a HFS diet later in life. IMPACT: The key message of this article is that neonatal maternal separation and a postweaning high-fat/high-sucrose diet increased the risk of an individual, particularly male, towards NAFLD in adult life. What this study adds to the existing literature includes the identification of two vulnerable differentially methylated regions in hepatic Cd36 promoters whose methylation levels very strongly negatively correlated with Cd36 mRNA. The impact of this article is that it provides an early-life environment-responsive gene/promoter methylation model and an animal model for furthering the mechanistic study on how the insults in early-life environment are “transmitted” into adulthood and caused NAFLD.