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- Title
Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith–Lemli–Opitz syndrome.
- Authors
Lindegaard, Marie L.; Wassif, Christopher A.; Vaisman, Boris; Amar, Marcelo; Wasmuth, Elizabeth V.; Shamburek, Robert; Nielsen, Lars B.; Remaley, Alan T.; Porter, Forbes D.
- 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 14C-cholesterol in corresponding mutant embryos. Disruption of either Abca1 or Sr-b1 decreased cholesterol transfer by ∼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.
- Publication
Human Molecular Genetics, 2008, Vol 17, Issue 23, p3806
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddn278