Changes in LXR signaling influence early-pregnancy lipogenesis and protect against dysregulated fetoplacental lipid homeostasis.
Nikolova, Vanya Papacleovoulou, Georgia Bellafante, Elena Borges Manna, Luiza Jansen, Eugene Baron, Silvère Abu-Hayyeh, Shadi Parker, Malcolm Williamson, Catherine
Nikolova, Vanya
Papacleovoulou, Georgia
Bellafante, Elena
Borges Manna, Luiza
Jansen, Eugene
Baron, Silvère
Abu-Hayyeh, Shadi
Parker, Malcolm
Williamson, Catherine
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Series / Report no.
Open Access
Type
Article
Language
en
Date of publication
2017-10-01
Year of publication
Research Projects
Organizational Units
Journal Issue
Title
Changes in LXR signaling influence early-pregnancy lipogenesis and protect against dysregulated fetoplacental lipid homeostasis.
Translated Title
Published in
Am J Physiol Endocrinol Metab 2017; 313(4):E463-72
Abstract
Human pregnancy is associated with enhanced de novo lipogenesis in the early stages followed by hyperlipidemia during advanced gestation. Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that stimulate de novo lipogenesis and also promote the efflux of cholesterol from extrahepatic tissues followed by its transport back to the liver for biliary excretion. Although LXR is recognized as a master regulator of triglyceride and cholesterol homeostasis, it is unknown whether it facilitates the gestational adaptations in lipid metabolism. To address this question, biochemical profiling, protein quantification, and gene expression studies were used, and gestational metabolic changes in T0901317-treated wild-type mice and Lxrab-/- mutants were investigated. Here, we show that altered LXR signaling contributes to the enhanced lipogenesis in early pregnancy by increasing the expression of hepatic Fas and stearoyl-CoA desaturase 1 (Scd1). Both the pharmacological activation of LXR with T0901317 and the genetic ablation of its two isoforms disrupted the increase in hepatic fatty acid biosynthesis and the development of hypertriglyceridemia during early gestation. We also demonstrate that absence of LXR enhances maternal white adipose tissue lipolysis, causing abnormal accumulation of triglycerides, cholesterol, and free fatty acids in the fetal liver. Together, these data identify LXR as an important factor in early-pregnancy lipogenesis that is also necessary to protect against abnormalities in fetoplacental lipid homeostasis.