Placental ABCA1 and ABCG1 transporters efflux cholesterol and protect trophoblasts from oxysterol induced toxicity.
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 alpha/beta ligands such as T0901317 increased ABCA1 and ABCG1 expression and enhanced cholesterol efflux to apoA-I and HDL, respectively, while treatment with pharmacological PPAR-alpha or -gamma 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.
Aye
Irving L M H
IL
School of Women's & Infants' Health, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth, Western Australia, Australia.
Waddell
Brendan J
BJ
Mark
Peter J
PJ
Keelan
Jeffrey A
JA
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D015153:Blotting, Western; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000009:adverse effects; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D006888:Hydroxycholesterols / Q000009:adverse effects*; D007124:Immunoenzyme Techniques; D007653:Ketocholesterols / Q000009:adverse effects*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; D007653:Ketocholesterols; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C007997:25-hydroxycholesterol; D002784:Cholesterol; C003001:7-ketocholesterol