Abstract-Although maternal-fetal cholesterol transfer may serve to compensate for insufficient fetal cholesterol biosynthesis under pathological conditions, it may have detrimental consequences under conditions of maternal hypercholesterolemia leading to preatherosclerotic lesion development in fetal aortas. Maternal cholesterol may enter fetal circulation by traversing syncytiotrophoblast and endothelial layers of the placenta. We hypothesized that endothelial cells (ECs) of the fetoplacental vasculature display a high and tightly regulated capacity for cholesterol release. Using ECs isolated from human term placenta (HPECs), we investigated cholesterol release capacity and examined transporters involved in cholesterol efflux pathways controlled by liver-X-receptors (LXRs). HPECs demonstrated 2.5-fold higher cholesterol release to lipid-free apolipoprotein (apo)A-I than human umbilical vein ECs (HUVECs), whereas both cell types showed similar cholesterol efflux to high-density lipoproteins (HDLs). Interestingly, treatment of HPECs with LXR activators increased cholesterol efflux to both types of acceptors, whereas no such response could be observed for HUVECs. In line with enhanced cholesterol efflux, LXR activation in HPECs increased expression of ATP-binding cassette transporters ABCA1 and ABCG1, while not altering expression of ABCG4 and scavenger receptor class B type I (SR-BI). Inhibition of ABCA1 or silencing of ABCG1 decreased cholesterol efflux to apoA-I (Ϫ70%) and HDL 3 (Ϫ57%), respectively. Immunohistochemistry localized both transporters predominantly to the apical membranes of placental ECs in situ. Thus, ECs of human term placenta exhibit unique, efficient and LXR-regulated cholesterol efflux mechanisms. We propose a sequential pathway mediated by ABCA1 and ABCG1, respectively, by which HPECs participate in forming mature HDL in the fetal blood. (Circ Res. 2009;104:600-608.)Key Words: maternal-fetal cholesterol transfer Ⅲ endothelial cells Ⅲ HDL Ⅲ liver X receptors C holesterol is indispensable during fetal development. 1 It has been long assumed that most, if not all, cholesterol required for fetal growth is synthesized de novo by the fetus itself, thus making it autonomous from maternal or placental cholesterol supply. However, several lines of evidence have cast doubt on this notion. 2,3 Fetuses that lack the ability to synthesize cholesterol, such as those with the Smith-LemliOpitz syndrome, are, nevertheless, born with low levels of tissue and plasma cholesterol, indicating that they have acquired maternal cholesterol in utero. 4 Recent exciting studies demonstrated a strong correlation between the size and number of atherosclerotic lesions in human fetal arteries with maternal cholesterol levels. 5,6 Moreover, maternal hypercholesterolemia also modified early predictors of cardiovascular disease in the offspring, thus corroborating the concept of developmental programming of adult disease in human. 7 Considering that progression of atherosclerosis in adults takes ages, these striking resu...

Liver X receptors (LXRs) are important regulators of cholesterol and lipid metabolism. LXR agonists have been shown to limit the cellular cholesterol content by inducing reverse cholesterol transport, increasing bile acid production, and inhibiting intestinal cholesterol absorption. Most of them, however, also increase lipogenesis via sterol regulatory element-binding protein-1c (SREBP1c) and carbohydrate response element-binding protein activation resulting in hypertriglyceridemia and liver steatosis. We report on the antiatherogenic properties of the steroidal liver X receptor agonist N,N-dimethyl-3b-hydroxy-cholenamide (DMHCA) in apolipoprotein E (apoE)-deficient mice. Long-term administration of DMHCA (11 weeks) significantly reduced lesion formation in male and female apoE-null mice. Notably, DMHCA neither increased hepatic triglyceride (TG) levels in male nor female apoE-deficient mice. ATP binding cassette transporter A1 and G1 and cholesterol 7a-hydroxylase mRNA abundances were increased, whereas SREBP1c mRNA expression was unchanged in liver, and even decreased in macrophages and intestine. Short-term treatment revealed even higher changes on mRNA regulation. Our data provide evidence that DMHCA is a strong candidate as therapeutic agent for the treatment or prevention of atherosclerosis, circumventing the negative side effects of other LXR agonists. Nuclear liver X receptors (LXRs) are involved in the control of cholesterol and lipid metabolism. LXRa (NR1H3) and LXRb (NR1H2) are sterol sensors that bind oxysterols to act as a transcriptional switch for the coordinated regulation of genes involved in cellular cholesterol homeostasis, cholesterol transport, catabolism, and absorption (1). In peripheral cells such as macrophages, LXRs are likely to coordinate a physiological response to cholesterol loading by regulating the transcription of several genes involved in cholesterol efflux and catabolism, including ATP-binding cassette (ABC)A1 and G1 (2-6).

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J. Neurochem. (2011) 119, 1016–1028. Abstract Currently, little is known about the role of intracellular triacylglycerol (TAG) lipases in the brain. Adipose triglyceride lipase (ATGL) is encoded by the PNPLA2 gene and catalyzes the rate‐limiting step of lipolysis. In this study, we investigated the effects of ATGL deficiency on brain lipid metabolism in vivo using an established knock‐out mouse model (ATGL‐ko). A moderate decrease in TAG hydrolase activity detected in ATGL‐ko versus wild‐type brain tissue was accompanied by a 14‐fold increase in TAG levels and an altered composition of TAG‐associated fatty acids in ATGL‐ko brains. Oil Red O staining revealed a severe accumulation of neutral lipids associated to cerebrovascular cells and in distinct brain regions namely the ependymal cell layer and the choroid plexus along the ventricular system. In situ hybridization histochemistry identified ATGL mRNA expression in ependymal cells, the choroid plexus, pyramidal cells of the hippocampus, and the dentate gyrus. Our findings imply that ATGL is involved in brain fatty acid metabolism, particularly in regions mediating transport and exchange processes: the brain–CSF interface, the blood–CSF barrier, and the blood–brain barrier.