Placental ABCA1 and ABCG1 expression in gestational disease: Pre-eclampsia affects ABCA1 levels in syncytiotrophoblasts
Introduction
The ATP-binding cassette (ABC) transporter family is important in the regulation of lipid homeostasis [1], [2], [3]. Two members of this family, ABCA1 and ABCG1, which efflux cholesterol, sphingolipids, phospholipids, and oxysterols, show high expression in the human placenta [3], [4], [5], [6], [7]. They likely play an important role in feto-maternal lipid transport and fetal lipid homeostasis. Lipid supply is indeed essential for the fetus. This is particularly important in the first trimester when the fetus is incapable of own cholesterol synthesis, but requires cholesterol for normal development such as for the formation of cell membranes and steroid hormone synthesis [8]. Correspondingly, Smith–Lemli–Opitz syndrome, the most common congenital disease of cholesterol synthesis caused by deficiency of 7-dehydrocholesterol reductase, is characterized by intrauterine growth restriction, fetal malformations and mental retardation [9]. Similarly, in a mouse model, functional loss of the lipid transporter ABCA1 resulted in not only a fetal loss of HDL-C and low serum cholesterol levels, but also intrauterine growth retardation, neonatal death and placental malformation with severe structural abnormalities [10].
Maternal cholesterol destined to the fetal circulation has to be transported across two barriers in the placenta, the villous syncytiotrophoblast and villous fetal endothelial cells, where both ABCA1 and ABCG1 have been described [5], [7]. The exact mechanisms of action and directionalities of transplacental lipid exchange through these two transporters are not fully understood yet. Synergistic functions are suggested by differential localization of ABCA1 and ABCG1 in the villous syncytiotrophoblast: ABCA1 in the apical cell membrane indicates a role in lipid exchange between maternal blood and the placental syncytiotrophoblast, while ABCG1 in the basolateral cell membrane, which in the mature placenta is in close proximity to fetal endothelial cells, may regulate lipid transport to or from the fetus [3], [5], [6], [11]. Moreover, ABCA1 and ABCG1 were described to interactively efflux cholesterol from fetal endothelial cells to apoA-I, apoE and HDL [7]. Furthermore, up-regulation of both ABCA1 and ABCG1 expression was found to be associated with increased transplacental cholesterol transport in a murine model [12], [13]. Other functions of placental ABCA1 in addition to feto-maternal lipid exchange are suggested by expression analyses demonstrating a pleiotropic localization of ABCA1 in multiple placental compartments such as the villous cytotrophoblast, villous macrophages (Hofbauer cells), mesenchymal cells of villi and chorionic plate, amnion epithelial cells and decidual cells [5].
As ABCA1 and ABCG1 emerge to be relevant for fetal and placental development, it seems likely that they may also be involved in gestational disease. However, studies analyzing their expression in pathological pregnancies are rare. The first gestational disease where ABCA1 expression levels were assessed was antiphospholipid syndrome, characterized by recurrent spontaneous miscarriages and thromboembolic events. Placental ABCA1 mRNA and protein levels were found to be reduced compared to controls [4]. Moreover, scarce studies exist on pre-eclampsia (PE), a pregnancy-specific disease defined by hypertension and proteinuria and showing an association with maternal hyperlipidemia. Based on different study designs and methodological approaches, variable results were reported, ranging from increased or unchanged to decreased placental ABCA1 expression in PE compared to normal controls [4], [14], [15]. To our knowledge data on other gestational diseases do not exist.
Therefore, the aim of the present study was to comprehensively characterize the placental ABCA1 and ABCG1 transcript and protein expression in common and important gestational diseases at the tissue, cellular and subcellular level and to associate findings with placental lipid content.
Section snippets
Patients and sample collection
The study was approved by the local ethic institutional review board. Placental tissue samples from caesarean sections (n = 72) were collected after obtaining informed consent from pregnant women at the Department of Obstetrics and Gynecology, University Hospital, Inselspital Bern, Switzerland. Exclusion criteria were multiple pregnancies, fetal death, infectious diseases and structural as well as chromosomal abnormalities. Cases were assigned to different groups: controls, preterm controls,
ABCA1 and ABCG1 mRNA expression in gestational diseases
As a prerequisite for adequate mRNA expression analysis, 7 reference genes (β-actin, glyceraldehyde 3-phosphate, β2-microglobulin, mitochondrial ribosomal protein L19, TATA box binding protein, ubiquitin (UBQ), and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide (YWHAZ)) were tested for their stability in placental diseases. Based on various methods of calculation, the results revealed that UBQ and YWHAZ were the most stably expressed reference genes in
Discussion
This study significantly extends current knowledge on the expression of placental lipid transporters in gestational disease by comprehensively assessing ABCA1 and ABCG1, two transporters originating from the same family and exhibiting similar and complementary functions, at the transcript and protein levels using various complementary methods in a selection of frequent and important pregnancy disorders. Of note, ABCA1, but not ABCG1 mRNA expression was dependent on gestational age, showing
Acknowledgments
The study was supported by the Swiss National Science Foundation grant 320030-119984 (to C.A.), Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Switzerland and the SwissLife Jubiläumsstiftung. The authors thank Michael Lüthi for expert help in mRNA analysis and immunohistochemical stainings, and Dr. Liudmila Nikitina for contributing to the sampling of placental tissues. Furthermore, the authors are grateful to Rene Gentinetti for his technical expertise in
References (32)
- et al.
Transport of lipids by ABC proteins: interactions and implications for cellular toxicity, viability and function
Chem Biol Interact
(2009) - et al.
Placental ABCA1 expression is reduced in primary antiphospholipid syndrome compared to pre-eclampsia and controls
Placenta
(2007) - et al.
Expression and localization pattern of ABCA1 in diverse human placental primary cells and tissues
Placenta
(2011) - et al.
Placental ABCA1 and ABCG1 transporters efflux cholesterol and protect trophoblasts from oxysterol induced toxicity
Biochim Biophys Acta
(2010) - et al.
Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency
Am J Pathol
(2000) - et al.
Localisation of ABCA1 in first trimester and term placental tissues
Placenta
(2010) - et al.
Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols
J Biol Chem
(2000) - et al.
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?
Placenta
(2010) - et al.
New birthweight and head circumference centiles for gestational ages 24 to 42 weeks
Early Hum Dev
(1987) - et al.
RNA degradation differentially affects quantitative mRNA measurements of endogenous reference genes in human placenta
Placenta
(2013)
Simultaneous preparation of paired, syncytial, microvillous and basal membranes from human placenta
Biochim Biophys Acta
Phosphatidylethanolamine in Trypanosoma brucei is organized in two separate pools and is synthesized exclusively by the Kennedy pathway
J Biol Chem
Expression and localization of ATP binding cassette transporter A1 (ABCA1) in first trimester and term human placenta
Placenta
Measurement of housekeeping genes in human placenta
Placenta
Revisiting the housekeeping genes of human placental development and insufficiency syndromes
Placenta
Evaluation of housekeeping genes in placental comparative expression studies
Placenta
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These authors contributed equally.