Fetal lipid metabolism is regulated by the Liver X Receptor (LXR) in mice

Abstract

The Liver X Receptors LXRa/ß are vitally important in regulating cholesterol and fatty acid metabolism in the adult. Aim of this study was to elucidate the role of LXR in the fetal mouse liver. Pregnant C57BL/6 mice or Lxra+/− mice crossed heterozygously were fed a diet containing the synthetic LXR agonist T0901317 from E10.5 until delivery. In fetuses and dams, gene expression and lipid levels were monitored. In the mouse fetus, hepatic expression of LXR target genes (e.g., Srebp1c, Fas and Abcg5) is low during gestation and increases after birth. Lxra itself is expressed at ~40 % of adult levels, whereas the expression of Lxrb is 2.5‐3 times higher than in adult control liver. Upon administration of T0901317, LXR target genes are activated in the fetal liver: expression of the cholesterol transporter Abcg5 is 45 times induced. Expression of Srebp1c and Fas is increased 2.0‐ to 5.3‐fold and 1.7‐ to 2.0‐fold, respectively. Consequently, triglyceride concentrations in fetal liver and plasma are raised up to 2.7‐ and 1.5‐fold. Cholesterol levels in plasma are doubled upon treatment, whereas hepatic cholesterol concentrations are unchanged. In Lxra−/− fetuses, these changes are reduced but not absent.ConclusionLxra and Lxrß are functionally active in fetal mouse liver when stimulated with the synthetic agonist T0901317. Similar to adult mice, cholesterol homeostasis and de novo lipogenesis can be influenced experimentally by administration of this agonist.Supported by the Dutch Heart Foundation (2004T048).