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

Hum Mol Genet. 2008 Dec 1;17(23):3806-13. doi: 10.1093/hmg/ddn278. Epub 2008 Sep 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Biological Transport
  • Cholesterol / metabolism*
  • Female
  • Humans
  • Hydrocarbons, Fluorinated / therapeutic use
  • Lipoproteins / genetics
  • Lipoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Placenta / metabolism*
  • Placental Circulation
  • Pregnancy
  • Smith-Lemli-Opitz Syndrome / embryology
  • Smith-Lemli-Opitz Syndrome / metabolism*
  • Smith-Lemli-Opitz Syndrome / therapy*
  • Sulfonamides / therapeutic use
  • Uterus / metabolism*

Substances

  • ABCA1 protein, human
  • ABCG1 protein, mouse
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters
  • Hydrocarbons, Fluorinated
  • Lipoproteins
  • Sulfonamides
  • T0901317
  • Cholesterol