Effects of Dietary Cholesterol on Plasma Lipoproteins in Smith-Lemli-Opitz Syndrome

Merkens, Louise S.; Connor, William E.; Linck, Leesa M.; Lin, Don S.; Flavell, Donna P; Steiner, Robert D.

doi:10.1203/01.pdr.0000141522.14177.4f

Cited by 24 publications

(22 citation statements)

References 45 publications

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“…The ability to obtain exogenous cholesterol could have a great impact upon fetuses that are cholesterol deficient, such as those with inborn errors in sterol synthesis, or those with reduced uterine blood flow and nutrient delivery, as occurs during intrauterine growth restriction (IUGR). Since HDL from sterol-deficient fetuses may be of abnormal composition and possibly low concentration [53,54], the question arises: Is plasma, and specifically HDL, from steroldeficient fetuses able to efflux cholesterol? We had a unique opportunity to determine if HDL from a cholesterol-deficient SLOS fetus was able to act as a cholesterol acceptor from trophoblasts.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…However, this does not preclude the possibility that differences in some of the more minor protein constituents of HDL could have an effect. Finally, the SLOS HDL particles could have a modified, more accepting structure due to the likely presence of 7-and 8-DHC; previous studies have shown that HDL will carry about the same percentage of 7-and 8-DHC as that in the whole plasma [53].Since 7-and 8-DHC can affect membrane structure and function [57,58], it is possible that they can also affect the ability to accept cholesterol from exogenous sources.It should be noted that the properties of HDL which make them better acceptors of cholesterol are somewhat dependent upon the mechanism responsible for the efflux. There are four major processes by which cholesterol is effluxed from cells: ABCA1-mediated, SR-BI-mediated, ABCG1-mediated, and simple diffusion down a concentration gradient [59,60].…”

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confidence: 99%

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

Jenkins

Merkens

Tubb

et al. 2008

Molecular Genetics and Metabolism

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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...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Jenkins

Merkens

Tubb

et al. 2008

Molecular Genetics and Metabolism

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“…The focus of treatment has been dietary, with the goal of providing supplementary cholesterol (such as egg yolk and cream). While improved growth, reduced photosensitivity and increased nerve conduction velocity have been documented, other benefits are largely anecdotal (18,22).…”

Section: Discussionmentioning

confidence: 99%

A Case of Smith-Lemli-Opitz Syndrome, Defect of Cholesterol Biosynthesis

Domizio¹,

Pallotta

Romanelli³

et al. 2006

Int J Immunopathol Pharmacol

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We report the case of a child with Smith-Lemli-Opitz Syndrome. The pregnancy was complicated by prenatal growth retardation. The baby was admitted to the Neonatal Intensive Care Unit of Chieti when she was five months old. She showed postnatal growth retardation, trouble sucking and swallowing, microcefaly and multiple major and minor malformations, including characteristic facial features and 2–3 syndactyly of the toes. We found correlations between multiple congenital malformations, failure to thrive and low plasmatic cholesterol measurement.

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“…By measuring total sterols in lipoproteins and plasma on both cholesterol-free and high cholesterol diets, Merkens et al (17), in this issue, not only attempted to answer this question, but also expanded our knowledge regarding the underlying sterol abnormalities in SLOS. In addition, they analyzed the distribution of cholesterol, 7-DHC, and 8-DHC in lipoproteins, and evaluated the affect of the apolipoprotein E genotype on the response to dietary cholesterol.…”

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confidence: 99%

Cholesterol in Childhood: Friend or Foe?: Commentary on the article by Merkens et al. on page 726

Irons

2004

Pediatr Res

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Effects of Dietary Cholesterol on Plasma Lipoproteins in Smith-Lemli-Opitz Syndrome

Cited by 24 publications

References 45 publications

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

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

A Case of Smith-Lemli-Opitz Syndrome, Defect of Cholesterol Biosynthesis

Cholesterol in Childhood: Friend or Foe?: Commentary on the article by Merkens et al. on page 726

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