Fetal gender and gestational age differentially affect PCSK9 levels in intrauterine growth restriction

Pecks, Ulrich; Rath, Werner; Maass, Nicolaì; Berger, B; Lueg, I; Farrokh, André; Farrokh, Sabrina; Eckmann-Scholz, Christel

doi:10.1186/s12944-016-0365-6

Cited by 26 publications

(19 citation statements)

References 28 publications

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“…LDLR and LDL uptake. LDLR was early described in the placenta 16,40 ; however, only two reports showed the in situ localization of LDLR in placental tissue 17,41 . In agreement with both papers, our confocal microscopy images of the whole placenta showed that LDLR was expressed mainly in the placental syncytiotrophoblast layer and suggest that the localization could be predominantly in the apical membrane, which requires confirmation with specific markers for this syncytiotrophoblast membrane in the same section of tissue.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol uptake and efflux are impaired in human trophoblast cells from pregnancies with maternal supraphysiological hypercholesterolemia

Fuenzalida

Cantin

Kallol

et al. 2020

Sci Rep

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Maternal physiological (MpH) or supraphysiological hypercholesterolaemia (MSpH) occurs during pregnancy. Cholesterol trafficking from maternal to foetal circulation requires the uptake of maternal LDL and HDL by syncytiotrophoblast and cholesterol efflux from this multinucleated tissue to ApoA-I and HDL. We aimed to determine the effects of MSPH on placental cholesterol trafficking. Placental tissue and primary human trophoblast (pHt) were isolated from pregnant women with total cholesterol <280 md/dL (MPH, n = 27) or ≥280 md/dL (MSPH, n = 28). The lipid profile in umbilical cord blood from MpH and MSpH neonates was similar. the abundance of LDL receptor (LDLR) and HDL receptor (SR-Bi) was comparable between MSpH and MpH placentas. However, LDLR was localized mainly in the syncytiotrophoblast surface and was associated with reduced placental levels of its ligand ApoB. in pHt from MSpH, the uptake of LDL and HDL was lower compared to MpH, without changes in LDLR and reduced levels of SR-BI. Regarding cholesterol efflux, in MSPH placentas, the abundance of cholesterol transporter ABCA1 was increased, while ABCG1 and SR-BI were reduced. In PHT from MSPH, the cholesterol efflux to ApoA-I was increased and to HDL was reduced, along with reduced levels of ABCG1, compared to MPH. Inhibition of SR-BI did not change cholesterol efflux in PHT. The TC content in PHT was comparable in MpH and MSpH cells. However, free cholesterol was increased in MSpH cells. We conclude that MSPH alters the trafficking and content of cholesterol in placental trophoblasts, which could be associated with changes in the placenta-mediated maternal-to-foetal cholesterol trafficking. During the progress of human pregnancy, the concentrations of total cholesterol (TC) and low-(LDL) rises in a physiological (maternal physiological hypercholesterolemia, MPH) 1,2 or supraphysiological (maternal supraphysiological hypercholesterolemia, MSPH) 3,4 way. MSPH is determined in women with TC levels above a cutoff value of 280-300 mg/dL at term of pregnancy or above the 75th percentile for the different trimesters of pregnancy 1-6. Endothelial dysfunction of the macro-and the microvascular vessels of the placenta 4,7-9 as well as development of atherosclerosis in the foetal aorta 1,2,6 has been described in pregnancies with MSPH and increased LDL levels. This information suggest that MSPH could be related to the development of cardiovascular disease in the offspring later in life 2,6,10,11. Despite the increased maternal TC and LDL concentrations, the levels of TC and triglycerides (Tg) of neonates from MSPH pregnancies are comparable to those from MPH pregnancies, suggesting a possible regulation of placental maternal-to-foetal cholesterol trafficking across the placenta 7,12 .

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Section: Discussionmentioning

confidence: 99%

Cholesterol uptake and efflux are impaired in human trophoblast cells from pregnancies with maternal supraphysiological hypercholesterolemia

Fuenzalida

Cantin

Kallol

et al. 2020

Sci Rep

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“…Several studies, including our own, have reported diminished fetal cholesterol concentrations in IUGR [17–23]. Characterizing umbilical cord blood sterol profiles in IUGR and normally grown fetuses we aimed at a deeper understanding of cholesterol metabolism during fetal development and impaired fetal growth.…”

Section: Discussionmentioning

confidence: 99%

“…In IUGR, cholesterol concentration in fetal blood is low [17–23]. In particular, the high-density lipoprotein (HDL) fraction, which is the main cholesterol acceptor and dominant lipoprotein in the fetus, is diminished by about 50% when compared to appropriately grown fetuses [17].…”

Section: Introductionmentioning

confidence: 99%

Estimating fetal cholesterol synthesis rates by cord blood analysis in intrauterine growth restriction and normally grown fetuses

et al. 2019

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BackgroundCholesterol is an essential component in human development. In fetuses affected by intrauterine growth restriction (IUGR), fetal blood cholesterol levels are low. Whether this is the result of a reduced materno-fetal cholesterol transport, or due to low fetal de novo synthesis rates, remains a matter of debate. By analyzing cholesterol interbolites and plant sterols we aimed at deeper insights into transplacental cholesterol transport and fetal cholesterol handling in IUGR with potential targets for future therapy. We hypothesized that placental insufficiency results in a diminished cholesterol supply to the fetus.MethodsVenous umbilical cord sera were sampled post-partum from fetuses delivered between 24 weeks of gestation and at full term. IUGR fetuses were matched to 49 adequate-for-age delivered preterm and term neonates (CTRL) according to gestational age at delivery. Cholesterol was measured by gas chromatography-flame ionization detection using 5a-cholestane as internal standard. Cholesterol precursors and synthesis markers, such as lanosterol, lathosterol, and desmosterol, the absorption markers, 5α-cholestanol and plant sterols, such as campesterol and sitosterol, as well as enzymatically oxidized cholesterol metabolites (oxysterols), such as 24S- or 27-hydroxycholesterol, were analyzed by gas chromatography-mass spectrometry, using epicoprostanol as internal standard for the non-cholesterol sterols and deuterium labeled oxysterols for 24S- and 27-hydroxycholesterol.ResultsMean cholesterol levels were 25% lower in IUGR compared with CTRL (p < 0.0001). Lanosterol and lathosterol to cholesterol ratios were similar in IUGR and CTRL. In relation to cholesterol mean, desmosterol, 24S-hydroxycholesterol, and 27-hydroxycholesterol levels were higher by 30.0, 39.1 and 60.7%, respectively, in IUGR compared to CTRL (p < 0.0001). Equally, 5α-cholestanol, campesterol, and β-sitosterol to cholesterol ratios were higher in IUGR than in CTRL (17.2%, p < 0.004; 33.5%, p < 0.002; 29.3%, p < 0.021).ConclusionsCholesterol deficiency in IUGR is the result of diminished fetal de novo synthesis rates rather than diminished maternal supply. However, increased oxysterol- and phytosterol to cholesterol ratios suggest a lower sterol elimination rate. This is likely caused by a restricted hepatobiliary function. Understanding the fetal cholesterol metabolism is important, not only for neonatal nutrition, but also for the development of strategies to reduce the known risk of future cardiovascular diseases in the IUGR fetus.

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“…Hence, the diagnosis of IUGR is based ideally on the antenatal observation of a deceleration of fetal growth velocity by serial sonographic measurements showing a “crossing of percentiles” or other antenatal parameters of fetal well-being [ 22 , 36 ]. Evidence is increasing that IUGR is a heterogeneous disorder that can be subdivided into clinical presentation of concomitant preeclampsia and early onset or late onset IUGR with a cut-off at 32 to 34 weeks of gestation [ 2 , 37 ]. Both, preeclampsia and increased resistance of the umbilical arteries (as indicated by resistance index/pulsatility index in Doppler sonography) are often associated with severe early onset IUGR.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E Genotype in Very Preterm Neonates with Intrauterine Growth Restriction: An Analysis of the German Neonatal Network Cohort

Norda

Rausch

Orlikowsky

et al. 2017

BioMed Research International

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Aim. Cord blood of intrauterine growth restricted (IUGR) neonates displays lipid changes towards atherosclerotic profiles. Apolipoprotein E (ApoE) and its isoforms (e2, e3, and e4) are involved in the regulation of lipid metabolism. Specifically, ApoE e4 has been associated with atherosclerotic diseases, while e2 has a favorable effect. We therefore hypothesized that ApoE e4 haplotype is frequently observed in IUGR neonates and contributes to impaired fetal growth and the association of IUGR with cardiovascular and metabolic diseases later in life. Methods. A cohort of 4885 preterm infants (≥22+0 and <32+0 weeks of gestation and birth weight below 1500 g) from the GNN study cohort was analyzed. Neonates were categorized into subgroups of <3rd, 3rd–10th, and >10th birth weight percentile. Analysis of the single nucleotides rs429358 and rs7412, identifying the ApoE genotype, was carried out using TaqMan® SNP genotyping assays. The proportional odds model was used to assess data. Results. No association was found between genotype and birth weight percentiles in each of the subgroups. Conclusion. ApoE genotype and low birth weight depict two distinct risk factors for cardiovascular disease without being directly associated.

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Fetal gender and gestational age differentially affect PCSK9 levels in intrauterine growth restriction

Cited by 26 publications

References 28 publications

Cholesterol uptake and efflux are impaired in human trophoblast cells from pregnancies with maternal supraphysiological hypercholesterolemia

Cholesterol uptake and efflux are impaired in human trophoblast cells from pregnancies with maternal supraphysiological hypercholesterolemia

Estimating fetal cholesterol synthesis rates by cord blood analysis in intrauterine growth restriction and normally grown fetuses

Apolipoprotein E Genotype in Very Preterm Neonates with Intrauterine Growth Restriction: An Analysis of the German Neonatal Network Cohort

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