Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome.
Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome.
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DOI：
10.1093/hmg/ddn278
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Porter FD
中科院分区：
文献类型：
--
作者：
Lindegaard ML;Wassif CA;Vaisman B;Amar M;Wasmuth EV;Shamburek R;Nielsen LB;Remaley AT;Porter FD
Smith-Lemli-Opitz综合征（SLOS）患者出生时有多种先天性异常。提供出生后胆固醇补充剂;然而，它不能纠正由于子宫内胆固醇缺乏引起的发育畸形。增加胆固醇从母体循环到胎儿循环的转运可能会减轻先天性畸形。胆固醇转运蛋白Abca 1、Abcg 1和Sr-b1存在于胎盘中;然而，它们在胎盘转运中的潜在作用尚未确定。在小鼠中，表达分析表明，Abca 1和Abcg 1转录增加两到三倍之间的胚胎天13.5和18.5胎盘组织，而Sr-b1的表达下降。为了研究Abca 1，Abcg 1和Sr-b1的功能作用，我们测量了相应突变胚胎中14 C-胆固醇的母胎转移。Abca 1或Sr-b1的破坏使胆固醇转移减少约30%。相反，破坏Abcg 1没有影响。用LXR激动剂TO 901317治疗怀孕的C57 Bl/6雌性小鼠，可增加Abca 1的表达和母胎胆固醇向胎儿的转移。在不能从头合成胆固醇的SLOS小鼠模型（Dhcr 7 −/−）中，在子宫内用TO 901317处理导致Dhcr 7 −/−胚胎中胆固醇含量增加。我们的数据支持这一假设，即Abca 1，可能Sr-b1，有助于运输母体胆固醇发育中的胎儿。此外，我们表明，作为一个原则的证据，调节母胎胆固醇转运有潜力在子宫内治疗SLOS。
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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影响因子：
3.8
作者：
Jenkins, Katie T.;Merkens, Louise S.;Woollett, Laura A.
通讯作者：
Woollett, Laura A.
DOI：
10.1002/tera.1420410403
发表时间：
1990-04-01
期刊：
TERATOLOGY
影响因子：
--
作者：
JOLLIE, WP
通讯作者：
JOLLIE, WP
影响因子：
30.8
作者：
Orsó, E;Broccardo, C;Schmitz, G
通讯作者：
Schmitz, G
影响因子：
9.3
作者：
Langmann, T;Mauerer, R;Schmitz, G
通讯作者：
Schmitz, G
影响因子：
15.9
作者：
Miettinen, HE;Rayburn, H;Krieger, M
通讯作者：
Krieger, M