Localization and regulation of the human very low density lipoprotein/apolipoprotein-E receptor: trophoblast expression predicts a role for the receptor in placental lipid transport

Abstract

The very low density lipoprotein/apolipoprotein-E receptor (VLDLR) is the newest member of the low density lipoprotein receptor (LDLR) family. Very little is known about VLDLR localization and regulation. Immunohistochemical analysis of human placenta with a specific polyclonal antibody detected VLDLR in syncytiotrophoblast and intermediate trophoblast cells. VLDLR transcripts were also localized in these cells by in situ hybridization histochemistry. In addition, VLDLR messenger RNA (mRNA) was detected in villous core endothelial cells and cells appearing to be Hofbauer cells. Northern blot analysis of placenta revealed a 2.6-fold increase in VLDLR mRNA at term compared to that in the first trimester. The regulation of VLDLR expression was studied in JEG-3 and BeWo choriocarcinoma cells, two trophoblast-derived cell lines. Treatment of these cells with 8-bromo-cAMP caused a profound suppression of VLDLR message, whereas LDLR transcripts were increased. Incubation of JEG-3 cells with 25-hydroxycholesterol did not lead to sterol negative feedback on VLDLR gene expression, unlike LDLR mRNA, which declined markedly. Insulin (200 mg/L) up-regulated VLDLR message in JEG-3 cells 2-fold, as did the fibrate hypolipidemic drug, clofibric acid. We conclude that 1) VLDLR is expressed in human placental trophoblast cells in a pattern consistent with a role in placental lipid transport; 2) VLDLR expression is high at term relative to that in the first trimester; and 3) the trophoblast VLDLR is subject to down-regulation by cAMP and up-regulation by insulin and fibrate hypolipidemic drugs.

The Very Low-density Lipoprotein (VLDL) Receptor: Characterization and Functions as a Peripheral Lipoprotein Receptor

“…On the other hand, insulin and clofibrate (hypolipidemic drugs) upr e g u l a t e d V L D L r e c e p t o r e x p r e s s i o n . 2 5 -hydroxycholesterol did not lead to sterol negative feedback on VLDL receptor expression (30). The VLDL receptor mRNA in adipose tissue and muscle was increased by 14-day gemfibrozil treatment in rabbits, indicating that the enhanced VLDL receptor expression was one of the mechanisms of the lipid-lowering effect of fibrate (31).…”

Effect of placental function on fatty acid requirements during pregnancy

“…The human placental microvillous membrane contains specific binding sites for the lipoporoteins (VLDL, LDL and HDL), which transport TG and other esterified lipid (Cummings et al, 1982;Naoum et al, 1987;Wittmaack et al, 1995). The presence of lipoprotein lipase activity (Rothwell & Elphick, 1982;Shafrir & Barash, 1987;Kaminsky et al, 1991;Bonet et al, 1992) allows the production of NEFA from TG.…”

Trophoblast‐like human choriocarcinoma cells serve as a suitable in vitro model for selective cholesteryl ester uptake from high density lipoproteins

“…The fact that the placenta binds and internalizes maternal lipoproteins both in vivo and in vitro [8] suggests the existence of functionally intact lipoprotein receptors [2][3][4][5][6][7][8][9][10][11]. The presence of active lipoprotein receptors in the yolk sac, the placenta and placenta-derived cells support internalization of cholesterol-rich maternal lipoproteins [8].…”