Changes in LXR signaling influence early-pregnancy lipogenesis and protect against dysregulated fetoplacental lipid homeostasis

TY - JOUR

T1 - Changes in LXR signaling influence early-pregnancy lipogenesis and protect against dysregulated fetoplacental lipid homeostasis

AU - Nikolova, Vanya

AU - Papacleovoulou, Georgia

AU - Bellafante, Elena

AU - Borges Manna, Luiza

AU - Jansen, Eugene

AU - Baron, Silvère

AU - Abu-Hayyeh, Shadi

AU - Parker, Malcolm G

AU - Williamson, Catherine

N1 - Copyright © 2017, American Journal of Physiology-Endocrinology and Metabolism.

PY - 2017/10

Y1 - 2017/10

N2 - 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 which 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 LXRα, β(-/-) 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 which is also necessary to protect against abnormalities in fetoplacental lipid homeostasis.

AB - 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 which 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 LXRα, β(-/-) 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 which is also necessary to protect against abnormalities in fetoplacental lipid homeostasis.

KW - Journal Article

U2 - 10.1152/ajpendo.00449.2016

DO - 10.1152/ajpendo.00449.2016

M3 - Article

C2 - 28420650

SN - 0193-1849

SP - ajpendo.00449.2016

JO - AMERICAN JOURNAL OF PHYSIOLOGY: ENDOCRINOLOGY AND METABOLISM

JF - AMERICAN JOURNAL OF PHYSIOLOGY: ENDOCRINOLOGY AND METABOLISM

ER -