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?
OBJECTIVE
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.


METHODS
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.


METHODS
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.
Plösch
T
T
Dept Pediatrics, University Medical Center Groningen, University of Groningen, Center for Liver, Digestive and Metabolic Diseases, Groningen, The Netherlands. t.plosch@med.umcg.nl
Gellhaus
A
A
van Straten
E M E
EM
Wolf
N
N
Huijkman
N C A
NC
Schmidt
M
M
Dunk
C E
CE
Kuipers
F
F
Winterhager
E
E
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000924:Anticholesteremic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000008:administration & dosage / Q000378:metabolism*; D010920:Placenta / Q000166:cytology / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000494:pharmacology; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010100:Oxygen; D012313:RNA; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides