Document Detail

Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome.
MedLine Citation:
PMID:  18775956     Owner:  NLM     Status:  MEDLINE    
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.
Marie L Lindegaard; Christopher A Wassif; Boris Vaisman; Marcelo Amar; Elizabeth V Wasmuth; Robert Shamburek; Lars B Nielsen; Alan T Remaley; Forbes D Porter
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-09-05
Journal Detail:
Title:  Human molecular genetics     Volume:  17     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-10     Completed Date:  2008-12-29     Revised Date:  2010-09-21    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  3806-13     Citation Subset:  IM    
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.
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MeSH Terms
ATP-Binding Cassette Transporters / genetics,  metabolism*
Biological Transport
Cholesterol / metabolism*
Hydrocarbons, Fluorinated / therapeutic use
Lipoproteins / genetics,  metabolism
Mice, Inbred C57BL
Placenta / metabolism*
Placental Circulation
Smith-Lemli-Opitz Syndrome / embryology,  metabolism*,  therapy*
Sulfonamides / therapeutic use
Uterus / metabolism*
Grant Support
Z01 HD000139-11/HD/NICHD NIH HHS
Reg. No./Substance:
0/ABCG1 protein, mouse; 0/ATP binding cassette transporter 1; 0/ATP-Binding Cassette Transporters; 0/Hydrocarbons, Fluorinated; 0/Lipoproteins; 0/Sulfonamides; 0/TO-901317; 57-88-5/Cholesterol

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