title: Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome.
abstract: Patients with Smith-Lemli-Opitz syndrome (SLOS) are born with multiple congenital abnormalities. Postnatal cholesterol supplementation is provided; however, it cannot correct developmental malformations due to in utero cholesterol deficit. Increased transport of cholesterol from maternal to fetal circulation might attenuate congenital malformations. The cholesterol transporters Abca1, Abcg1, and Sr-b1 are present in placenta; however, their potential role in placental transport remains undetermined. In mice, expression analyses showed that Abca1 and Abcg1 transcripts increased 2-3-fold between embryonic days 13.5 and 18.5 in placental tissue; whereas, Sr-b1 expression decreased. To examine the functional role of Abca1, Abcg1 and Sr-b1 we measured the maternal-fetal transfer of (14)C-cholesterol in corresponding mutant embryos. Disruption of either Abca1 or Sr-b1 decreased cholesterol transfer by approximately 30%. In contrast, disruption of the Abcg1 had no effect. Treatment of pregnant C57Bl/6 female mice with TO901317, an LXR-agonist, increased both Abca1 expression and maternal-fetal cholesterol transfer to the fetus. In an SLOS mouse model (Dhcr7(-/-)), which is incapable of de novo synthesis of cholesterol, in utero treatment with TO901317 resulted in increased cholesterol content in Dhcr7(-/-) embryos. Our data support the hypothesis that Abca1, and possibly Sr-b1, contributes to transport maternal cholesterol to the developing fetus. Furthermore, we show, as a proof of principle, that modulating maternal-fetal cholesterol transport has potential for in utero therapy of SLOS.
authors.affiliation: Section on Molecular Dysmorphology, Eunice Kennedy Schriver National Institute of Child Health and Human Development, National Heart, Lung and Blood Institute, NIH, DHHS, Bethesda, MD, USA. marie.s.lindegaard@dadlnet.dk
authors.forename: Marie L
authors.initials: ML
authors.lastname: Lindegaard
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.forename: Boris
authors.initials: B
authors.lastname: Vaisman
authors.forename: Marcelo
authors.initials: M
authors.lastname: Amar
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: Wasmuth
authors.forename: Robert
authors.initials: R
authors.lastname: Shamburek
authors.forename: Lars B
authors.initials: LB
authors.lastname: Nielsen
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000627:therapeutic use; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000378:metabolism*; D021041:Placental Circulation; D011247:Pregnancy; D019082:Smith-Lemli-Opitz Syndrome / Q000196:embryology / Q000378:metabolism* / Q000628:therapy*; D013449:Sulfonamides / Q000627:therapeutic use; D014599:Uterus / Q000378:metabolism*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D008074:Lipoproteins; D013449:Sulfonamides; C577836:ABCA1 protein, human; C487540:ABCG1 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
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