Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome

Marie L. Lindegaard, Christopher A. Wassif, Boris Vaisman, Marcelo Amar, Elizabeth V. Wasmuth, Robert Shamburek, Lars B. Nielsen, Alan T. Remaley, Forbes D. Porter

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3806-3813
Number of pages8
JournalHuman molecular genetics
Volume17
Issue number23
DOIs
StatePublished - 2008
Externally publishedYes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Molecular Biology

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