Placental heme receptor LRP1 correlates with the heme exporter FLVCR1 and neonatal iron status

Abstract

LDL receptor-related protein 1 (LRP 1) is a transmembrane receptor highly expressed in human placenta. It was recently found to be the receptor for heme and its plasma binding protein hemopexin and is integral to systemic heme clearance. Little is known about systemic concentrations of hemopexin during pregnancy and whether maternal hemopexin and placental LRP1 contributes to fetal iron homeostasis during pregnancy. We hypothesized that placental LRP1 would be up-regulated in maternal/neonatal iron insufficiency and would be related to maternal circulating hemopexin. Placental LRP1 expression was assessed in 57 pregnant adolescents (14–18 y) in relation to maternal and cord blood iron status indicators [hemoglobin, serum ferritin, transferrin receptor], the iron regulatory hormone hepcidin and serum hemopexin. Hemopexin at mid-gestation correlated positively with hemoglobin at mid-gestation (r = 0.35, P = 0.02) and hemopexin at delivery correlated positively with cord hepcidin (r = 0.37, P = 0.005). Placental LRP1 protein expression was significantly higher in women who exhibited greater decreases in serum hemopexin from mid-gestation to term (r = 0.28, P = 0.04). Significant associations were also found between placental LRP1 protein with cord hepcidin (r = − 0.29, P = 0.03) and placental heme exporter FLVCR1 (r = 0.34, P = 0.03). Our data are consistent with a role for placental heme iron utilization in supporting fetal iron demands.

Vitamin D status is inversely associated with anemia and serum erythropoietin during pregnancy

“…Serum was stored at 2808C until analysis. Results on calcitropic hormones (23,24), fetal bone growth (7), bone turnover and osteoprotegerin (25), changes in maternal bone quality across gestation (26), maternal iron status, erythropoietin and hepcidin (22), pica behaviors (27), placental iron transporter expression (28)(29)(30), maternal diet and fetal adiposity (31), and placental vitamin D hydroxylase expression (24) in this cohort have been published. To estimate habitual dietary intake during pregnancy, study personnel trained by research dietitians at the University of Rochester's Clinical and Translational Science Center administered 24-h dietary recalls to study participants during their scheduled study visits.…”

Iron Nutriture of the Fetus, Neonate, Infant, and Child

“…After binding to iron (Fe 3+ ) on the apical side of the syncytiotrophoblast, holotransferrin with its bound iron is internalized and the iron is released into the cytoplasm. The trophoblasts may also take up non-transferrin-bound iron via ZIP8 or ZIP14 [40, 41] and heme iron via LRP1 [42]. No matter which pathway it uses to enter the cell, all non-heme iron is released from the basal side of syncytio-trophoblast via ferroportin (FPN).…”

Maternal iron status during pregnancy compared with neonatal iron status better predicts placental iron transporter expression in humans

“…The following primers were designed through Roche Applied Science Universal Probe Library using the National Center for Biotechnology Information (Bethesda, MD, USA) sequence ID and purchased from Integrated DNA Technologies (Coralville, IA, USA): DMT1 (divalent metal transporter): forward: 5′‐CAC CGT CAG TAT CCC AAG GT‐3′, reverse: 5′‐CAT GTC TGA GCC GAT GAT AGC‐3′; TfR1 (transferrin receptor 1): forward: 5′‐ACC TGT CCA GAC AAT CTC CAG‐3′, reverse: 5′‐TGT TTT CCA GTC AGA GGG ACA‐3′; ferroportin: forward: 5′‐TTA CCA GAA AAC CCC AGC TC‐3′, reverse: 5′‐CAG GGG TTT TGG CTC AGT AT‐3′; HEPHL1 (zyklopen): forward: 5′‐ATT CCA AGT GCC CAT GAC A‐3′, reverse: 5′‐CCT GGA CCG GAT CTT TTA GG‐3′;HAMP (hepcidin):forward:5′‐CTG TTT TCC CAC AAC AGA CG‐3′, reverse: 5′‐TTC GCC TCT GGA ACA TGG‐3′; FLVCR1: forward: 5′‐CCC AAA GAG GTG TCC ACA G‐3′, reverse: 5′‐GGT AGC AAA AAG CCA ACT GC‐3′; FLVCR2 (feline leukemia virus subgroup C receptor 2): forward: 5′‐AGC AAA CAA AGA AAC TCT TGA GAA C‐3′,reverse:5′‐TTT GCT GGT GTT GCT CTC C‐3′; SLC46A1 [solute carrier family 46 (folate transporter), member 1 or proton‐coupled folate transporter]: forward: 5′‐CAT CCC GGC TGT TCT GAT‐3′,reverse:5′‐CTG CTG GAA CTC GAG GTG A‐3′; and SLC48A1 [solute carrier family 48 (heme transporter) member 1 or heme‐responsive gene 1 protein homolog (HRG1)]: forward: 5′‐CTG CAC CTT CCT CGT GCT‐3′, reverse: 5′‐AAG GCC CAC TTG AAG GAA AT‐3′. Primer sequences used for LRP1 and β‐actin have been published (25). Plate‐to‐plate variation was controlled by normalizing gene expression to β‐actin and a control placenta by using the ΔΔ C t method: Δ C t = C t (target) ‐ Ct (β‐actin); ΔΔ C t = Δ C t (sample) ‐ Δ C t (control placenta); fold change = 2 ‐ ΔΔCt .…”

“…Placental protein was isolated, homogenized, and quantified as previously reported (25, 32), and abundance of placental Fe transporters was measured by Western blot. Methods and materials used to measure ferroportin, FLVCR1, and LRP1 have been published (25, 32). For the remaining placental proteins, protein isolates were run on SDS‐PAGE gels and transferred to PVDF fluorescence membranes (Millipore, Billerica, MA, USA).…”