The Liver X Receptor (LXR) and its Target Gene ABCA1 are Regulated Upon Low Oxygen in Human Trophoblast Cells: A Reason for Alterations in Preeclampsia?

Plösch, T.; Gellhaus, A.; van Straten, E.M.E.; Wolf, N.; Huijkman, N.C.A.; Schmidt, M.; Dunk, C.E.; Kuipers, F.; Winterhager, E.

doi:10.1016/j.placenta.2010.07.009

« Previous Next »Placenta
Volume 31, Issue 10 , Pages 910-918, October 2010

The Liver X Receptor (LXR) and its Target Gene ABCA1 are Regulated Upon Low Oxygen in Human Trophoblast Cells: A Reason for Alterations in Preeclampsia?

T. Plösch
- Center for Liver, Digestive and Metabolic Diseases, Dept. Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Corresponding author at: Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Tel.: +31 50 3614865; fax: +31 50 3611746.
- T.P. and A.G. contributed equally.
A. Gellhaus
- Institute of Molecular Biology, University Hospital of Essen, Essen, Germany
- T.P. and A.G. contributed equally.
E.M.E. van Straten
- Center for Liver, Digestive and Metabolic Diseases, Dept. Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
N. Wolf
- Institute of Molecular Biology, University Hospital of Essen, Essen, Germany
N.C.A. Huijkman
- Center for Liver, Digestive and Metabolic Diseases, Dept. Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
M. Schmidt
- Dept. Gynecology, University Hospital of Essen, Essen, Germany
C.E. Dunk
- Dept. Obstetrics and Gynecology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada
F. Kuipers
- Center for Liver, Digestive and Metabolic Diseases, Dept. Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Center for Liver, Digestive and Metabolic Diseases, Dept. Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
E. Winterhager
- Institute of Molecular Biology, University Hospital of Essen, Essen, Germany

Accepted 20 July 2010. published online 16 August 2010.

Abstract

Objectives

The Liver X receptors (LXR) alpha and beta and their target genes such as the ATP-binding cassette (ABC) transporters have been shown to be crucially involved in the regulation of cellular cholesterol homeostasis. The aim of this study was to characterize the role of LXR alpha/beta in the human placenta under normal physiological circumstances and in preeclampsia.

Study design

We investigated the expression pattern of the LXRs and their target genes in the human placenta during normal pregnancy and in preeclampsia. Placental explants and cell lines were studied under different oxygen levels and pharmacological LXR agonists.

Main outcome measures

Gene expressions (Taqman PCR) and protein levels (Western Blot) were combined with immunohistochemistry to analyze the expression of LXR and its target genes.

Results

In the human placenta, LXRA and LXRB expression increased during normal pregnancy. This was paralleled by the expression of their prototypical target genes, e.g., the cholesterol transporter ABCA1. Interestingly, early-onset preeclamptic placentae revealed a significant upregulation of ABCA1. Culture of JAr trophoblast cells and human first trimester placental explants under low oxygen lead to increased expression of LXRA and ABCA1 which was further enhanced by the LXR agonist T0901317.

Conclusions

LXRA together with ABCA1 are specifically expressed in the human placenta and can be regulated by hypoxia. Deregulation of this system in early preeclampsia might be the result of placental hypoxia and hence might have consequences for maternal-fetal cholesterol transport.

Keywords: Maternal-fetal lipid transport, ABCA1, LXRA, Cholesterol, Placenta, Preeclampsia

Abbreviations: ABCA1, ATP-binding cassette transporter, sub-family A, member 1, ABCG1/4/5/8, ATP-binding cassette transporter, sub-family G, member 1/4/5/8, APOA1, apolipoprotein a1, FASN, fatty acid synthase, HDL, high-density lipoprotein, LDL, low-density lipoprotein, LXRA, liver X receptor alpha (nuclear receptor sub-family 1, group H, member 3), LXRB, liver X receptor beta (nuclear receptor sub-family 1, group H, member 2), RXR, retinoid X receptor (nuclear receptor sub-family 2, group b, member 1), SRBI, scavenger receptor class B, member 1, SREBP1C, sterol regulatory element binding protein-1c