Preeclampsia is a pregnancy-specific multisystem disorder characterized by hypertension and proteinuria. Accentuated maternal hyperlipidemia, especially high serum levels of oxidized low-density lipoprotein (oxLDL), is one of the features of preeclampsia. We previously reported that lectin-like oxidized LDL receptor 1 (LOX-1) expression was decreased in preeclamptic placentas. Here, we show that decreased LOX-1 expression is associated with low expression of adenosine triphosphate-binding cassette transporter A1 (ABCA1) in the placenta. The ABCA1 mediates cellular efflux of cholesterol, and liver X receptors (LXRs) are its predominant transcriptional regulators. Both ABCA1 and LXR expressions were significantly lower in preeclamptic placentas than those in normal controls. Oxidized LDL upregulated ABCA1 expression, while LOX-1 blockade resulted in the alleviation of increasing ABCA1 messenger RNA in JAR cells. These results suggest that low LOX-1 expression may lead to insufficient oxLDL uptake, thereby contributing to reduced LXR activation and decreased ABCA1 expression in preeclamptic placentas.
PotterJMNestelPJ. The hyperlipidemia of pregnancy in normal and complicated pregnancies. Am J Obstet Gynecol. 1979;133(2):165–170.
4.
SattarNBendomirABerryCShepherdJGreerIAPackardCJ. Lipoprotein subfraction concentrations in preeclampsia: pathogenic parallels to atherosclerosis. Obstet Gynecol. 1997;89(3):403–408.
5.
UzunHBenianAMadazliRTopcuogluMAAydinSAlbayrakM. Circulating oxidized low-density lipoprotein and paraoxonase activity in preeclampsia. Gynecol Obstet Investig. 2005;60(4):195–200.
6.
BranchDWMitchellMDMillerEPalinskiWWitztumJL. Pre-eclampsia and serum antibodies to oxidised low-density lipoprotein. Lancet. 1994;343(8898):645–646.
7.
NishimuraMNaitoS. Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet. 2005;20(6):452–477.
8.
LangmannTMauererRZahnAReal-time reverse transcription-PCR expression profiling of the complete human ATP-binding cassette transporter superfamily in various tissues. Clin Chem. 2003;49(2):230–238.
9.
Christiansen-WeberTAVolandJRWuYFunctional 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;157(3):1017–1029.
10.
JanowskiBAWillyPJDeviTRFalckJRMangelsdorfDJ. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996;383(6602):728–731.
11.
ChigusaYTatsumiKKondohEDecreased lectin-like oxidized LDL receptor 1 (LOX-1) and Low Nrf2 activation in placenta are involved in preeclampsia. J Clin Endocrinol Metab. 2012;97(10): E1862–1870.
12.
BhattacharjeeJIettaFGiacomelloEExpression and localization of ATP binding cassette transporter A1 (ABCA1) in first trimester and term human placenta. Placenta. 2010;31(5):423–430.
13.
AyeILWaddellBJMarkPJKeelanJA. Placental ABCA1 and ABCG1 transporters efflux cholesterol and protect trophoblasts from oxysterol induced toxicity. Biochim Biophys Acta. 2010;1801(9):1013–1024.
14.
StefuljJPanzenboeckUBeckerTHuman endothelial cells of the placental barrier efficiently deliver cholesterol to the fetal circulation via ABCA1 and ABCG1. Circulation Res. 2009;104(5):600–608.
15.
PloschTGellhausAvan StratenEMThe 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;31(10):910–918.
16.
AlbrechtCSoumianSTetlowNPlacental ABCA1 expression is reduced in primary antiphospholipid syndrome compared to pre-eclampsia and controls. Placenta. 2007;28(7):701–708.
17.
PostonL. Leptin and preeclampsia. Semin Reprod Med. 2002;20(2):131–138.
18.
MaynardSEMinJYMerchanJExcess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Investig. 2003;111(5):649–658.
19.
LindegaardMLWassifCAVaismanBCharacterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome. Hum Mol Genet. 2008;17(23):3806–3813.
20.
BodziochMOrsoEKluckenJThe gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet. 1999;22(4):347–351.
21.
Weedon-FekjaerMSJohnsenGMAnthonisenEHExpression of liver X receptors in pregnancies complicated by preeclampsia. Placenta. 2010;31(9):818–824.
22.
JosephSBCastrilloALaffitteBAMangelsdorfDJTontonozP. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003;9(2):213–219.
23.
TerasakaNHiroshimaAKoieyamaTT-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice. FEBS Lett. 2003;536(1-3):6–11.
24.
LevinNBischoffEDDaigeCLMacrophage liver X receptor is required for antiatherogenic activity of LXR agonists. Arterioscler Thromb Vasc Biol. 2005;25(1):135–142.
25.
PengDHiipakkaRAReardonCAGetzGSLiaoS. Differential anti-atherosclerotic effects in the innominate artery and aortic sinus by the liver X receptor agonist T0901317. Atherosclerosis. 2009;203(1):59–66.
26.
SchusterGUPariniPWangLAccumulation of foam cells in liver X receptor-deficient mice. Circulation. 2002;106(9):1147–1153.
27.
RobertsonWBKhongTYBrosensIDe WolfFSheppardBLBonnarJ. The placental bed biopsy: review from three European centers. Am J Obstet Gynecol. 1986;155(2):401–412.
28.
WhitneyKDWatsonMAGoodwinBLiver X receptor (LXR) regulation of the LXRalpha gene in human macrophages. J Biol Chem. 2001;276(47):43509–43515.
