Human Molecular Genetics Advance Access published online on September 5, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn278
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Published by Oxford University Press 2008
Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome
1 Section on Molecular Dysmorphology, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Schriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD, USA 2 Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, National Heart, Lung and Blood Institute, NIH, DHHS, Bethesda, MD, USA 3 Departments of Clinical Biochemistry, Rigshospitalet and Biomedical Sciences, University of Copenhagen, Denmark
* Corresponding author: Marie L. Lindegaard, MD, Current address: Dept. of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark, Phone: +45 3545 2957, Fax: +45 3545 2524, Email: marie.s.lindegaard{at}dadlnet.dk
Received July 11, 2008; Revised August 15, 2008; Accepted September 1, 2008
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 two to three-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 14C-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 a 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.
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