van Straten EME, Bloks VW, Huijkman NCA, Baller JFW, van Meer H, Lü tjohann D, Kuipers F, Plö sch T. The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction. Am J Physiol Regul Integr Comp Physiol 298: R275-R282, 2010. First published November 4, 2009 doi:10.1152/ajpregu.00413.2009.-Prenatal nutrition as influenced by the nutritional status of the mother has been 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 influence fetal lipid metabolism by inducing epigenetic adaptations. Pregnant C57BL/6J mice were exposed to a protein-restriction protocol (9% vs. 18% casein). Shortly before birth, dams and fetuses were killed. To identify putative epigenetic changes, CG-dinucleotiderich region in the promoter of a gene (CpG island) methylation microarrays were performed on DNA isolated from fetal livers. Two hundred four gene 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 cholesterol and fatty acid metabolism. The mRNA level of Lxra was reduced by 32% in fetal liver upon maternal protein restriction, whereas expression of the Lxr target genes Abcg5/Abcg8 was reduced by 56% and 51%, respectively, measured by real-time quantitative PCR. The same effect, although less pronounced, was observed in the fetal intestine. 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. It is tempting to speculate that perinatal nutrition may influence adult lipid metabolism by DNA methylation, which may contribute to the epidemiological relation between perinatal/neonatal nutrition and adult disease.programming; epigenetics; CpG island methylation microarray AN OVERWHELMING BODY OF EVIDENCE links fetal (mal)nutrition to the development of chronic diseases at adult age [developmental origins of health and disease hypothesis (4, 5)]. Epidemiological data show that children small for gestational age, who were undernourished during intrauterine development, have a higher risk of developing cardiovascular diseases or the metabolic syndrome in adulthood (3). In humans, fetal malnutrition is related to external factors (starvation, malnutrition, drug consumption of the mother) or to internal factors, such as placental dysfunction leading to reduced routing of nutrients to the fetus (32).Knowledge of underlying mechanisms of metabolic programming may help to design strategies to halt the current epidemic in metabolic diseases. For this purpose, several animal mo...
