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 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.

The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

“…Reduced fatty acid transport can also directly compromise placental function, owing to excess accumulation and subsequent oxidative stress (Jarvie et al, 2010). The high fetal demand for cholesterol in late gestation is met by both placental transfer from the maternal circulation and by fetal de novo synthesis (Lindegaard et al, 2008;Yoshida and Wada, 2005). Therefore, changes in placental cholesterol uptake and transfer are more likely to affect the fetal brain via further impact on placental function.…”

Maternal ABCA1 genotype is associated with severity of Smith–Lemli–Opitz syndrome and with viability of patients homozygous for null mutations

“…41 In DHCR7 À/ À mice, it was shown that disruption of ABCA1 is associated with a 30% decrease of cholesterol transfer to the fetus, suggesting that ABCA1 plays a crucial role in placental cholesterol transfer. 42 In this setting, it is important that ABCA1 has no effective ATPase activity and therefore does not directly facilitate the transport of cholesterol from mother to child. Rather, it has a regulatory role in this process.…”

Translational Research in Pediatrics IV: Solid Tissue Collection and Processing

“…[180][181][182][183] Tissue that would otherwise have been discarded, including placentas and umbilical cords, can be obtained for research purposes because their collection poses little risk to the patients. [185][186][187] The placenta has been used in child-health research to investigate preeclampsia, 188 maternal obesity, 63 endocrine disruptors, 189 attention-deficit/hyperactivity disorder, 64 Smith-Lemli-Opitz syndrome, 190 and vertical virus transmissions. 65,66 Blood drawn from umbilical cord veins has been used for regenerative medicine 72 and stem cell research.…”