Enhanced placental cholesterol efflux by fetal HDL in Smith–Lemli–Opitz syndrome

Abstract

Previous studies from this laboratory have shown that maternal-derived cholesterol can be effluxed from trophoblasts to fetal HDL and plasma. We had the opportunity to study for the first time the ability of HDL and plasma from a fetus with the Smith-Lemli-Opitz syndrome (SLOS) to efflux cholesterol from trophoblasts. It was unclear whether cholesterol could be effluxed to fetuses with SLOS since lipoprotein levels are often very low. To answer this question, cord blood was collected from the placentas of an SLOS fetus and unaffected fetuses just after delivery. Plasma cholesterol concentrations were very low in the affected fetus; cholesterol, 7-dehydrocholesterol, and 8-dehydocholesterol concentrations were 14.1, 4.5, and 5.2 mg/dl, respectively. The HDL from the fetal SLOS effluxed ≈50% more cholesterol from a trophoblast cell line, were smaller in size, and had a lower cholesterol to phospholipid ratio as compared to HDL from unaffected fetuses or adults. Plasma from the SLOS fetus effluxed cholesterol to a similar percentage as unaffected fetal plasma or adult plasma, possibly due to fewer HDL particles as demonstrated in previous SLOS patients. These novel data demonstrate that the cholesteroldeficient SLOS fetus is able to obtain cholesterol from trophoblasts at a time when cholesterol is playing a critical role in development, and has implications for design of treatments for cholesterol deficiency syndromes as well as understanding of prenatal cholesterol transport in humans. KeywordsFetus; Trophoblast; BeWo cells; Pregnancy; Cholesterol transport Smith-Lemli-Opitz syndrome (SLOS) is a metabolic disorder that presents with a spectrum of congenital abnormalities. Individuals with a severe phenotype have many congenital abnormalities and mental retardation whereas those with a mild phenotype may have only subtle learning disorders and minor dysmorphic features [1][2][3]. The biochemical cause of this syndrome is a reduction in the activity of the enzyme 7-dehydrocholesterol-Δ7- [4,5], which converts 7-dehydrocholesterol (7-DHC) to cholesterol, due to mutations in DHCR7 [6][7][8]. As might be expected, SLOS is characterized by a reduction in cholesterol and an increase in cholesterol precursors, including 7-and 8-DHC. Recent studies demonstrate that the incidence of this syndrome may be much greater than previously believed at a predicted incidence of 1:1590-1:13,500 [9,10], though observed incidence is lower (perhaps 1 in 20,000 births). The discrepancy in observed versus predicted incidence is likely due in part to pregnancy loss as well as undiagnosed mild cases. Nevertheless, SLOS is probably the second most prevalent, potentially lethal, recessive genetic condition behind cystic fibrosis with an incidence of 1:2500 [11]. The congenital malformations associated with this disease can begin to appear as early as 3 weeks postconception when Sonic Hedgehog (SHH) is needed for patterning of the forebrain [12,13], since sterols activate SHH [14][15][16] and sterol deficiency is thought to play a rol...

Treatment of Smith–Lemli–Opitz syndrome and other sterol disorders

“…Manipulation of maternal cholesterol mass and maternal to fetal cholesterol transport have the potential to improve outcomes in fetuses affected with SLOS. Fetuses with SLOS are similar to unaffected fetuses in their capacity to extract cholesterol from trophoblasts [Jenkins et al, 2008], and cholesterol supplementation in early pregnancy has potential therapeutic efficacy [Woollett, 2011]. Modulation of maternal to fetal cholesterol transport also has the potential for in utero treatment of SLOS.…”

Smith–Lemli–Opitz syndrome

“…This suggests that there are factors in addition to the SLOS genotype that significantly influence the clinical severity. Other genes involved in cholesterol synthesis, transport or regulation are likely to modify outcomes, for example, (1) differences in the conversion of 7-DHC to abnormal steroids, oxysterols or neuroactive sterols, (2) the supply of cholesterol during development regulated by the activity of the ABCA1 cholesterol transporter (86), (3) maternal ApoE genotype that affects cholesterol transfer from the mother to the fetus (97), or (4) the size of the HDL particles (smaller size in cord blood from affected fetus than in controls) that may influence the transport of maternal cholesterol to the fetus (98). Occasionally, only one mutation has been found in the coding region and around the splice sites of the exons.…”

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

“…If, however, maternal-fetal cholesterol transport could be induced prior to closure of the fetal blood-brain-barrier, neurological and behavioral abnormalities might be ameliorated. Recently, data were published suggesting that high density lipoprotein (HDL) particles from SLOS fetuses are better acceptors of cholesterol than HDL particles from normal fetuses (4), raising the possibility that if more cholesterol could be transferred to the fetal circulation the fetus would in fact be capable of accepting it and circulating it in HDL particles.…”