Activation of the liver x receptor (LXR) in utero does not affect lipid metabolism in mouse offspring upon high fat dietary challenge

Abstract

The Liver X Receptors LXRα/ß are vitally important in regulating cholesterol and fatty acid metabolism in the adult. Earlier studies by us have shown that prenatal exposure to a synthetic LXR agonist induces hyperlipidemia and hepatic steatosis in fetal mice. Aim of this study was to investigate effects of LXR activation in utero on lipid metabolism at a later age. Methods: Pregnant C57BL/6 mice were fed a diet containing the synthetic LXR agonist T0901317 from E10.5 until delivery. Pups were weaned onto chow. Pups received a high‐fat/high cholesterol (HFHC) diet or chow (C) from 6 till 8 weeks of age, after which hepatic gene expression and lipid levels were measured. Results: The HFHC diet led to 2‐ to 3‐fold increased hepatic triglyceride concentrations in male offspring. Plasma cholesterol concentrations were increased 1.6 times, while plasma triglyceride concentrations were unchanged. However, no differences between groups having received T0901317 or chow during gestation were observed. The HFHC diet led to induction of LXR target genes, but no effect of gestational T0901317 exposure was seen: expression of the cholesterol transporter Abcg8 was increased 2 times in both HFHC groups (with or without T0901317) whereas the expression of lipogenic genes Srebp1c and Scd1 were increased 2.5‐fold and 3‐fold, respectively in both HFHC groups. Conclusions: Fetal activation of LXR does not influence short‐term coping with a high‐fat/high cholesterol diet in young mice. Long‐term studies should elucidate whether fetal LXR activation exerts long‐lasting effects on the health of the offspring.Supported by the Dutch Heart Foundation (2004T048).