Lipids from Oxidized Low-Density Lipoprotein Modulate Human Trophoblast Invasion: Involvement of Nuclear Liver X Receptors

Abstract

Human embryonic implantation involves major invasion of the uterine wall and remodeling of the uterine arteries by extravillous cytotrophoblast cells (EVCT). Abnormalities in these early steps of placental development lead to poor placentation and fetal growth defects and are frequently associated with preeclampsia, a major complication of human pregnancy. We recently showed that oxidized low-density lipoproteins (oxLDLs) are present in situ in EVCT and inhibit cell invasion in a concentration-dependent manner. The aim of the present study was to better understand the mechanisms by which oxLDL modulate trophoblast invasion. We therefore investigated the presence of oxLDL receptors in our cell culture model of human invasive primary EVCT. We found using immunocytochemistry and immunoblotting that the lectin-like oxLDL receptor-1 was the scavenger receptor mainly expressed in EVCT and was probably involved in oxLDL uptake. We next examined the effect of low-density lipoprotein oxidative state on trophoblast invasion in vitro using EVCT cultured on Matrigel-coated Transwell. We demonstrated that only oxLDL containing a high proportion of oxysterols and phosphatidylcholine hydroperoxide derivatives that provide ligands for liver X receptor (LXR) and peroxisomal proliferator-activated receptor gamma (PPARgamma), respectively, reduced trophoblast invasion. We next investigated the presence and the role of these nuclear receptors and found that in addition to PPARgamma, human invasive trophoblasts express LXRbeta, and activation of these nuclear receptors by specific synthetic or natural ligands inhibited trophoblast invasion. Finally, using a PPARgamma antagonist, we suggest that LXRbeta, rather than PPARgamma, is involved in oxLDL-mediated inhibition of human trophoblast invasion in vitro.

Role of Nuclear Receptors Peroxisome Proliferator-Activated Receptors (PPARs) and Liver X Receptors (LXRs) in the Human Placental Pathophysiology

“…Furthermore, the 7-ketocholesterol inhibit extravillous cytotrophoblast invasion. The role of LXR ligands in the placenta was confirmed using the LXR agonist T0901317, demonstrating the role of this nuclear receptor and its ligands in modulating the human trophoblast invasion (Pavan et al, 2004).…”

“…A specific feature of human placentation is the high degree of trophoblast invasion, greater than in other mammals. T0901317 has been shown to inhibit the invasiveness of cultured cytotrophoblast cells in vitro (Pavan et al, 2004). In addition, LXR mediates the inhibitory effect of oxidized LDL on trophoblast invasiveness.…”

“…Moreover, oxysterols such as 25-hydroxycholesterol (25-OHC) and 7-ketocholesterol (7-ketoC) circulate at low concentrations in normal conditions, but increase in maternal plasma as pregnancy advances (Aye et al, 2011). At low concentrations (2.5 µM) the oxysterol 22 (R)-OHC was shown to prevent first trimester extravillous cytotrophoblast invasion through the liver X receptor (LXR) which recognizes oxysterols as endogenous ligands (Pavan et al, 2004;Fournier et al, 2008b). Furthermore, the 7-ketocholesterol inhibit extravillous cytotrophoblast invasion.…”

“…Noted that a new target gene, the long -chain acyl-coA synthetase 3 (ACSL3) was recently identified to illustrate the role of LXR as a regulator in fatty acid metabolism (Weedson-Fekjaer et al, 2010a). LXR has been demonstrated to be expressed in the placenta and in trophoblast-like cell lines, e.g., JAR and BeWo (Peet et al, 1998;WeedonFekjaer, 2005;Pavan et al, 2004). The increased fatty acid secretion by BeWo cells mediated by LXRs indicates its importance in placental lipid transport.…”

“…Several lines of evidence support the involvement of the LXR pathway in trophoblast biology. Firstly, trophoblast invasion is accompanied by an increased degradation of extracellular matrix proteins by members of the matrix metalloproteinases (MMPs) family (Caniggia et al,1997), and expression of matrix metalloprotease-9 (MMP9) is regulated in macrophages by a mechanism dependent on LXR activation (Castrillo et al, 2003); secondly, T0901317 and oxidized LDLs (oxLDL), rich in oxysterols, significantly reduce trophoblast invasion via a mechanism involving LXR (Pavan et al, 2004;Fournier et al, 2008;Bełtowski & Semczuk, 2010). Recently Aye et al have shown that oxysterols inhibit syncytialisation and differentiation of term placental trophoblasts by activating LXRs.…”