Cholesterol uptake and efflux are impaired in human trophoblast cells from pregnancies with maternal supraphysiological hypercholesterolemia

Maternal physiological (MPH) or supraphysiological hypercholesterolaemia (MSPH) occurs during pregnancy. Cholesterol trafficking from maternal to foetal circulation requires the uptake of maternal LDL and HDL by syncytiotrophoblast and cholesterol efflux from this multinucleated tissue to ApoA-I and HDL. We aimed to determine the effects of MSPH on placental cholesterol trafficking. Placental tissue and primary human trophoblast (PHT) were isolated from pregnant women with total cholesterol <280 md/dL (MPH, n = 27) or ≥280 md/dL (MSPH, n = 28). The lipid profile in umbilical cord blood from MPH and MSPH neonates was similar. The abundance of LDL receptor (LDLR) and HDL receptor (SR-BI) was comparable between MSPH and MPH placentas. However, LDLR was localized mainly in the syncytiotrophoblast surface and was associated with reduced placental levels of its ligand ApoB. In PHT from MSPH, the uptake of LDL and HDL was lower compared to MPH, without changes in LDLR and reduced levels of SR-BI. Regarding cholesterol efflux, in MSPH placentas, the abundance of cholesterol transporter ABCA1 was increased, while ABCG1 and SR-BI were reduced. In PHT from MSPH, the cholesterol efflux to ApoA-I was increased and to HDL was reduced, along with reduced levels of ABCG1, compared to MPH. Inhibition of SR-BI did not change cholesterol efflux in PHT. The TC content in PHT was comparable in MPH and MSPH cells. However, free cholesterol was increased in MSPH cells. We conclude that MSPH alters the trafficking and content of cholesterol in placental trophoblasts, which could be associated with changes in the placenta-mediated maternal-to-foetal cholesterol trafficking.