The Liver X‐Receptor (LXR) gene promoter is hypermethylated in a mouse model of prenatal protein restriction

Abstract

Prenatal nutrition, e.g., nutritional status of the mother, has been epidemiologically identified as a determinant of adult disease. Feeding low‐protein diets during pregnancy in rodents is a well‐established model to induce "programming" events in offspring. We hypothesized that protein restriction would induce epigenetic adaptations which would interfere with lipid metabolism. C57BL/6 mice were fed a protein restricted diet during pregnancy. At day 19.5 of pregnancy, dams and fetuses were sacrificed. CpG island methylation microarrays were performed on fetal liver DNA. 204 promoter regions were differentially methylated upon protein restriction. The liver X‐receptor (Lxr) alpha promoter was hypermethylated in protein‐restricted pups. Lxr alpha is a nuclear receptor critically involved in control of lipid metabolism. mRNA level of Lxra tended to be reduced in fetal liver upon maternal protein restriction, whereas expression of Lxr target genes were significantly reduced. In vitro methylation of a mouse Lxra‐promoter/luciferase expression cassette resulted in a 24‐fold transcriptional repression. Our study demonstrates that, in mice, protein restriction during pregnancy interferes with DNA methylation in fetal liver. Lxra is a target of differential methylation and Lxra transcription is dependent on DNA methylation. We suggest that prenatal nutrition may influence adult lipid metabolism by DNA methylation which may contribute to the epidemiological relation between prenatal/neonatal nutrition and adult disease.Supported by the Dutch Heart Foundation (2004T048).