Elsevier

Placenta

Volume 34, Issue 11, November 2013, Pages 1079-1086
Placenta

Placental ABCA1 and ABCG1 expression in gestational disease: Pre-eclampsia affects ABCA1 levels in syncytiotrophoblasts

https://doi.org/10.1016/j.placenta.2013.06.309Get rights and content

Abstract

Introduction

Transplacental feto-maternal lipid exchange through the ATP-binding cassette transporters ABCA1 and ABCG1 is important for normal fetal development. However, only scarce and conflicting data exist on the involvement of these transporters in gestational disease.

Methods

Placenta samples (n = 72) derived from common gestational diseases, including pre-eclampsia (PE), HELLP, intrauterine growth restriction (IUGR), intrahepatic cholestasis of pregnancy and gestational diabetes, were assessed for their ABCA1 and ABCG1 expression levels and compared to age-matched control placentas with qRT-PCR and immunohistochemistry. ABCA1 expression was additionally investigated with immunoblot in placental membrane vesicles. Furthermore, placental cholesterol and phospholipid contents were assessed.

Results

ABCA1 mRNA levels differed significantly between preterm and term control placentas (p = 0.0013). They were down-regulated in isolated PE and PE with IUGR (p = 0.0006 and p = 0.0012, respectively), but unchanged in isolated IUGR, isolated HELLP and other gestational diseases compared to gestational age-matched controls. Correspondingly, in PE, ABCA1 protein expression was significantly reduced in the apical membrane of the villous syncytiotrophoblast (p = 0.011) and in villous fetal endothelial cells (p = 0.036). Furthermore, in PE there was a significant increase in the placental content of total and individual classes of phospholipids which were partially correlated with diminished ABCA1 expression. Conversely, ABCG1 mRNA and protein levels were stable in the investigated conditions.

Conclusions

In gestational disease, there is a specific down-regulation of placental ABCA1 expression at sites of feto-maternal lipid exchange in PE. At a functional level, the increase in placental lipid concentrations provides indirect evidence of an impaired transport capacity of ABCA1 in this disease.

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)

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