Regulatory effects of synthetic liver X receptor- and peroxisome-proliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells

Panzenboeck, Ute; Kratzer, Ingrid; Sovic, Andrea; Wintersperger, Andrea; Bernhart, Eva; Hammer, Astrid; Malle, Ernst; Sattler, Wolfgang

doi:10.1016/j.biocel.2006.01.013

Cited by 53 publications

(49 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, our previous studies demonstrated that the apoA-I/ABCA1 pathway is also operative and inducible by LXR activation in porcine brain capillary ECs (pBCECs), which constitute the blood-brain barrier. 36,37 In contrast ECs from other vascular beds such as HUVECs (as confirmed the present study; Figure 1B) and/or human aortic ECs (HAECs) show only a poor ability to efflux cholesterol to lipid-free apoA-I. 23,38,39 Therefore, the apoA-I/ABCA1 pathway appears to be prominently active and regulated by LXR in ECs constituting blood-tissue and blood-blood barriers, ie, blood-brain and placental "barrier."…”

Section: Discussionsupporting

confidence: 80%

Human Endothelial Cells of the Placental Barrier Efficiently Deliver Cholesterol to the Fetal Circulation via ABCA1 and ABCG1

Štefulj

Panzenboeck²,

Becker

et al. 2009

Circulation Research

Self Cite

156

108

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 80%

Human Endothelial Cells of the Placental Barrier Efficiently Deliver Cholesterol to the Fetal Circulation via ABCA1 and ABCG1

Štefulj

Panzenboeck²,

Becker

et al. 2009

Circulation Research

Self Cite

156

108

View full text Add to dashboard Cite

show abstract

“…As found in previous studies [29,43,68], our present results suggest that nuclear receptors (RXRs, LXRs, and others) are promising drug targets for modulating the BBB's physiology and treating CNS pathologies.…”

Section: Discussionsupporting

confidence: 66%

“…We and others have previously reported that cholesterol exchange between the brain and the blood is mediated by several proteins expressed by the ECs composing the BBB [29,30,43,44]. In the absence of treatment, BLECs loaded with radioactive cholesterol were able to efflux a small proportion (0.86% in an HSA-only control condition) to the basolateral medium (the brain side, Fig.…”

Section: Cholesterol Efflux From Blecsmentioning

confidence: 99%

Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier

Kuntz

Candela

Saint-Pol

et al. 2015

JAD

View full text Add to dashboard Cite

Abstract.One of the prime features of Alzheimer's disease (AD) is the excessive accumulation of amyloid-␤ (A␤) peptides in the brain. Several recent studies suggest that this phenomenon results from the dysregulation of cholesterol homeostasis in the brain and impaired bidirectional A␤ exchange between blood and brain. These mechanisms appear to be closely related and are controlled by the blood-brain barrier (BBB) at the brain microvessel level. In animal models of AD, the anticancer drug bexarotene (a retinoid X receptor agonist) has been found to restore cognitive functions and decrease the brain amyloid burden by regulating cholesterol homeostasis. However, the drug's therapeutic effect is subject to debate and the exact mechanism of action has not been characterized. Therefore, the objective of this present study was to determine bexarotene's effects on the BBB. Using an in vitro model of the human BBB, we investigated the drug's effects on cholesterol exchange between abluminal and luminal compartments and the apical-to-basolateral transport of A␤ peptides across the BBB. Our results demonstrated that bexarotene induces the expression of ABCA1 but not ApoE. This upregulation correlates with an increase in ApoE2-, ApoE4-, ApoA-I-, and HDL-mediated cholesterol efflux. Regarding the transport of A␤ peptides, bexarotene increases the expression of ABCB1, which in turn decreases A␤ apical-to-basolateral transport. Our results showed that bexarotene not only promotes the cholesterol exchange between the brain and the blood but also decreases the influx of A␤ peptides across BBB, suggesting that bexarotene is a promising drug candidate for the treatment of AD.

show abstract

“…Further studies covering the influence of statins on SCARB1 regulatory mechanisms in liver and intestinal cells are still needed. Statins down-regulate liver X receptor (LXR) and up-regulate peroxisome proliferator activated receptor (PPAR) alpha in macrophages and hepatic tissues 42,43) , two nuclear receptors known to regulate SCARB1 expression positively 44,45) . It is possible that the activation by statins of these two regulatory mechanisms with opposite effects could explain the lack of effects by simvastatin and atorvastatin treatments in our experiments due to a compensatory mechanism; meanwhile, more investigation is needed in order to understand the effects of statins on hepatic and intestinal tissues.…”

mentioning

confidence: 99%

Influence of Polymorphisms and Cholesterol-Lowering Treatment on SCARB1 mRNA Expression

Cerda

Genvigir

Rodrigues

et al. 2011

JAT

View full text Add to dashboard Cite

Regulatory effects of synthetic liver X receptor- and peroxisome-proliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells

Cited by 53 publications

References 66 publications

Human Endothelial Cells of the Placental Barrier Efficiently Deliver Cholesterol to the Fetal Circulation via ABCA1 and ABCG1

Human Endothelial Cells of the Placental Barrier Efficiently Deliver Cholesterol to the Fetal Circulation via ABCA1 and ABCG1

Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier

Influence of Polymorphisms and Cholesterol-Lowering Treatment on SCARB1 mRNA Expression

Contact Info

Product

Resources

About