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.
Highlights
PREGNANCY IS A DYNAMIC STATE involving profound changes in the hormonal milieu of the mother that signal adaptations in maternal nutrient metabolism
To examine the impact of pregnancy on murine lipid metabolism, serum lipids were profiled in mice at different stages of pregnancy: day 7 postcoitum, corresponding to early pregnancy (EP), and days 10, 14, and 18 postcoitum, taken to represent advanced pregnancy (AP)
We examined whether the supraphysiological accumulation of free fatty acids in the serum of LXR double knockout (DKO) mice during advanced gestation could result from abnormalities in intestinal lipid absorption. mRNA quantification studies confirmed that Lxrab deficiency has no significant impact on the duodenal expression of key lipogenic targets [cluster of differentiation (Cd36), fatty acid transport protein (Fatp4), plasma membrane fatty acid binding protein (Fabp-pm), acetyl-CoA synthase 1 (Acs1), Dgat1, and Dgat2] in mice on day 18 of pregnancy
Summary
PREGNANCY IS A DYNAMIC STATE involving profound changes in the hormonal milieu of the mother that signal adaptations in maternal nutrient metabolism. These adaptations are necessary to ensure a continuous supply of essential metabolites to support the growth and the development of the fetus as well as to provide the mother with sufficient energy stores to meet the demands of pregnancy and prepare for lactation [15, 26]. Liver X receptors LXR␣ (NR1H3) and LXR (NR1H2) are oxysterol-activated nuclear receptors with key roles in the regulation of lipid metabolism. We hypothesized that alterations in LXR activity could contribute to the gestational adaptations in lipid metabolism during pregnancy. LXR MODULATES PREGNANCY ADAPTATIONS IN LIPID METABOLISM data suggest that LXR protects against abnormalities in fetoplacental lipid homeostasis during murine pregnancy
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