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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Characterization of placental cholesterol transport : ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome. / Lindegaard, Marie L; Wassif, Christopher A; Vaisman, Boris; Amar, Marcelo; Wasmuth, Elizabeth V; Shamburek, Robert; Nielsen, Lars Bo; Remaley, Alan T; Porter, Forbes D.

In: Human Molecular Genetics, Vol. 17, No. 23, 2008, p. 3806-13.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Lindegaard, ML, Wassif, CA, Vaisman, B, Amar, M, Wasmuth, EV, Shamburek, R, Nielsen, LB, Remaley, AT & Porter, FD 2008, 'Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome', Human Molecular Genetics, vol. 17, no. 23, pp. 3806-13. https://doi.org/10.1093/hmg/ddn278

APA

Lindegaard, M. L., Wassif, C. A., Vaisman, B., Amar, M., Wasmuth, E. V., Shamburek, R., Nielsen, L. B., Remaley, A. T., & Porter, F. D. (2008). Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome. Human Molecular Genetics, 17(23), 3806-13. https://doi.org/10.1093/hmg/ddn278

Vancouver

Lindegaard ML, Wassif CA, Vaisman B, Amar M, Wasmuth EV, Shamburek R et al. Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome. Human Molecular Genetics. 2008;17(23):3806-13. https://doi.org/10.1093/hmg/ddn278

Author

Lindegaard, Marie L ; Wassif, Christopher A ; Vaisman, Boris ; Amar, Marcelo ; Wasmuth, Elizabeth V ; Shamburek, Robert ; Nielsen, Lars Bo ; Remaley, Alan T ; Porter, Forbes D. / Characterization of placental cholesterol transport : ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 23. pp. 3806-13.

Bibtex

@article{83a60f0018cf4da0941934b8b4eabc8a,
title = "Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome",
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.",
keywords = "ATP-Binding Cassette Transporters, Animals, Biological Transport, Cholesterol, Female, Humans, Hydrocarbons, Fluorinated, Lipoproteins, Mice, Mice, Inbred C57BL, Placenta, Placental Circulation, Pregnancy, Smith-Lemli-Opitz Syndrome, Sulfonamides, Uterus",
author = "Lindegaard, {Marie L} and Wassif, {Christopher A} and Boris Vaisman and Marcelo Amar and Wasmuth, {Elizabeth V} and Robert Shamburek and Nielsen, {Lars Bo} and Remaley, {Alan T} and Porter, {Forbes D}",
year = "2008",
doi = "10.1093/hmg/ddn278",
language = "English",
volume = "17",
pages = "3806--13",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "23",

}

RIS

TY - JOUR

T1 - Characterization of placental cholesterol transport

T2 - ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome

AU - Lindegaard, Marie L

AU - Wassif, Christopher A

AU - Vaisman, Boris

AU - Amar, Marcelo

AU - Wasmuth, Elizabeth V

AU - Shamburek, Robert

AU - Nielsen, Lars Bo

AU - Remaley, Alan T

AU - Porter, Forbes D

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

KW - ATP-Binding Cassette Transporters

KW - Animals

KW - Biological Transport

KW - Cholesterol

KW - Female

KW - Humans

KW - Hydrocarbons, Fluorinated

KW - Lipoproteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Placenta

KW - Placental Circulation

KW - Pregnancy

KW - Smith-Lemli-Opitz Syndrome

KW - Sulfonamides

KW - Uterus

U2 - 10.1093/hmg/ddn278

DO - 10.1093/hmg/ddn278

M3 - Journal article

C2 - 18775956

VL - 17

SP - 3806

EP - 3813

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 23

ER -

ID: 38432361