Placental ABCA1 and ABCG1 transporters efflux cholesterol and protect trophoblasts from oxysterol induced toxicity |
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Authors: | Irving LMH Aye Brendan J Waddell Peter J Mark Jeffrey A Keelan |
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Institution: | 1. School of Women''s & Infants'' Health, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth, Western Australia, Australia;2. School of Anatomy & Human Biology, Faculty of Life and Physical Sciences, University of Western Australia, Perth, Western Australia, Australia |
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Abstract: | ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 mediate the efflux of cholesterol and other sterols. Both transporters are expressed on the fetal capillaries of the placenta and are involved in maternal-to-fetal cholesterol delivery. In this study, we report that ABCA1 and ABCG1 are also present on the syncytiotrophoblast, the maternal facing placental membrane. Syncytial ABCA1 expression is apical, suggesting a role in cholesterol efflux to the mother, while ABCG1 is expressed basolaterally indicating transport to the fetus. Silencing of ABCA1 expression in primary trophoblasts in culture, or pharmacological antagonism by glyburide, decreased cholesterol efflux to apolipoprotein A-I (apoA-I) compared to controls, while ABCG1-silencing decreased cholesterol efflux to high density lipoproteins (HDL). In contrast, treatment with endogenous or synthetic LXR α/β ligands such as T0901317 increased ABCA1 and ABCG1 expression and enhanced cholesterol efflux to apoA-I and HDL, respectively, while treatment with pharmacological PPAR-α or -γ ligands was without effect. Trophoblasts transfected with ABCA1 or ABCG1 siRNA were more sensitive to toxic oxysterols substrates (25-hydroxycholesterol and 7-ketocholesterol) compared to mock-transfected cells, while prior treatment with T0901317 reduced oxysterol-mediated toxicity. These results identify syncytial ABCA1 and ABCG1 as important, inducible cholesterol transporters which also prevent placental accumulation of cytotoxic oxysterols. |
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Keywords: | 7-ketoC 7-ketocholesterol 22(R)-OHC 22(R)-hydroxycholesterol 25-OHC 25-hydroxycholesterol ABC ATP-binding cassette ACAT acyl-coA:cholesterol acyltransferase apoA-I apolipoprotein A-I HDL high density lipoprotein LXR liver X receptor PPAR peroxisome proliferator-activated receptor siRNA small interfering RNA SLOS Smith&ndash Lemli&ndash Opitz Syndrome SR-BI scavenger receptor-BI |
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