Endocrine Abstracts

Introduction: Normal pregnancy is characterised by dyslipidaemia which progresses with gestational age as a consequence of the growing energy demands of the mother and developing fetus. Specifically, there is an increase in the maternal plasma cholesterol, triglyceride and phospholipid concentrations.

Liver X receptor (Lxr) is a nuclear receptor which promotes cholesterol clearance and de novo lipogenesis.

Hypothesis: We hypothesise that gestational dyslipidaemia is a result of pregnancy signals which modulate the activity of Lxr, thus altering the expression of Lxr target genes involved in the regulation of lipid homeostasis.

Methods and results: RNA studies in normal-chow-fed C57BL6 WT mice revealed that on day 7 post coitum (pcm) there was increased expression of Lxr target genes (e.g Scd-1, Cyp7a1, Abcg8), while on days 10, 14 and 18 pcm their expression was down-regulated. No gestational alterations in the mRNA and protein levels of Lxrα were observed. Attempting to reverse the gestational adaptations in lipid metabolism, we challenged pregnant mice with the Lxr agonist T0901317 through diet. Our results confirmed that the expression of the Lxr targets in pregnant T0901317-fed mice was significantly higher than in matched pregnant normal-chow-fed females. The gradual decrease in the expression of Lxr targets was maintained in the T0901317-fed pregnant mice but the magnitude of reduction was lower than that in normal-chow-fed mice. Biochemical profiling demonstrated that Lxr induction in pregnancy prevented hepatic and serum lipid maternal adaptations that were observed in normal pregnancy.

Conclusion: Our data reveal a gradual down-regulation of Lxr targets involved in hepatic lipogenesis and cholesterol transport following mouse placenta formation. Activation of Lxr not only blunted the reduction of these genes but also reversed the changes in hepatic and lipid profiles observed during normal murine pregnancy. Our results suggest that the adaptations in lipid metabolism during pregnancy are associated with a reduction in Lxr activity.