Bone morphogenetic protein 2 (BMP2) and BMP6 are key regulators of systemic iron homeostasis. All BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments, but nothing is known about how BMP2 or BMP6 homodimeric or heterodimeric precursor proteins are proteolytically activated. Here, we conducted in vitro cleavage assays, which revealed that BMP2 is sequentially cleaved by furin at two sites, initially at a site upstream of the mature ligand, and then at a site adjacent to the ligand domain, while BMP6 is cleaved at a single furin motif.
View Article and Find Full Text PDFBone morphogenetic protein 2 (BMP2) and BMP6 are key regulators of systemic iron homeostasis. All BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments, but nothing is known about how BMP2 or BMP6 homodimeric or heterodimeric precursor proteins are proteolytically activated. Here, we conducted in vitro cleavage assays, which revealed that BMP2 is sequentially cleaved by furin at two sites, initially at a site upstream of the mature ligand, and then at a site adjacent to the ligand domain, while BMP6 is cleaved at a single furin motif.
View Article and Find Full Text PDFIron-mediated induction of bone morphogenetic protein (BMP)6 expression by liver endothelial cells is essential for iron homeostasis regulation. We used multiple dietary and genetic mouse cohorts to demonstrate a minor functional role for the metal-ion transporter ZIP8 in regulating BMP6 expression under high-iron conditions.
View Article and Find Full Text PDFHepcidin is the master hormone governing systemic iron homeostasis. Iron regulates hepcidin by activating bone morphogenetic protein (BMP)6 expression in liver endothelial cells (LECs), but the mechanisms are incompletely understood. To address this, we performed proteomics and RNA-sequencing on LECs from iron-adequate and iron-loaded mice.
View Article and Find Full Text PDFHepcidin is the master regulator of systemic iron homeostasis. The bone morphogenetic protein (BMP) signaling pathway is a critical regulator of hepcidin expression in response to iron and erythropoietic drive. Although endothelial-derived BMP6 and BMP2 ligands have key functional roles as endogenous hepcidin regulators, both iron and erythropoietic drives still regulate hepcidin in mice lacking either or both ligands.
View Article and Find Full Text PDFPregnancy entails a large negative balance of iron, an essential micronutrient. During pregnancy, iron requirements increase substantially to support both maternal red blood cell expansion and the development of the placenta and fetus. As insufficient iron has long been linked to adverse pregnancy outcomes, universal iron supplementation is common practice before and during pregnancy.
View Article and Find Full Text PDFMany forms of anemia are caused or complicated by pathologic restriction of iron (Fe). Chronic inflammation and certain genetic mutations decrease the activity of ferroportin, the only Fe-exporter protein, so that endogenously recycled or nutritionally absorbed Fe cannot be exported to the extracellular Fe carrier protein transferrin for delivery to the bone marrow. Diminished ferroportin activity renders anemia correction challenging as Fe administered intravenously or through nutritional supplementation is trafficked through the ferroportin-transferrin axis.
View Article and Find Full Text PDFTransferrin receptor 1 (TfR1) performs a critical role in cellular iron uptake. Hepatocyte TfR1 is also proposed to influence systemic iron homeostasis by interacting with the hemochromatosis protein HFE to regulate hepcidin production. Here, we generated hepatocyte Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), either alone or together with Hfe knockout or β-thalassemia, to investigate the extent to which hepatocyte TfR1 function depends on HFE, whether hepatocyte TfR1 impacts hepcidin regulation by serum iron and erythropoietic signals, and its contribution to hepcidin suppression and iron overload in β-thalassemia.
View Article and Find Full Text PDFSystemic iron homeostasis is regulated by the hepatic hormone hepcidin to balance meeting iron requirements while limiting toxicity from iron excess. Iron-mediated induction of bone morphogenetic protein (BMP) 6 is a central mechanism for regulating hepcidin production. Liver endothelial cells (LECs) are the main source of endogenous BMP6, but how they sense iron to modulate BMP6 transcription and thereby hepcidin is uncertain.
View Article and Find Full Text PDFIn plasma, iron is normally bound to transferrin, the principal protein in blood responsible for binding and transporting iron throughout the body. However, in conditions of iron overload when the iron-binding capacity of transferrin is exceeded, non-transferrin-bound iron (NTBI) appears in plasma. NTBI is taken up by hepatocytes and other parenchymal cells via NTBI transporters and can cause cellular damage by promoting the generation of reactive oxygen species.
View Article and Find Full Text PDFIron balance is tightly controlled to provide adequate amounts of this essential nutrient, but to limit the adverse effects of excess iron. Key mediators of systemic iron homeostasis are the iron regulatory hormone hepcidin and its receptor, the iron export protein ferroportin. A new study by Mohammad et al.
View Article and Find Full Text PDFIron is essential for a healthy pregnancy, and iron supplementation is nearly universally recommended, regardless of maternal iron status. A signal of potential harm is the U-shaped association between maternal ferritin, a marker of iron stores, and risk of adverse pregnancy outcomes. However, ferritin is also induced by inflammation and may overestimate iron stores during inflammation or infection.
View Article and Find Full Text PDFIron homeostasis is tightly regulated to balance the iron requirement for erythropoiesis and other vital cellular functions, while preventing cellular injury from iron excess. The liver hormone hepcidin is the master regulator of systemic iron balance by controlling the degradation and function of the sole known mammalian iron exporter ferroportin. Liver hepcidin expression is coordinately regulated by several signals that indicate the need for more or less iron, including plasma and tissue iron levels, inflammation, and erythropoietic drive.
View Article and Find Full Text PDFIron disorders are associated with adverse pregnancy outcomes, yet iron homeostatic mechanisms during pregnancy are poorly understood. In humans and rodents, the iron-regulatory hormone hepcidin is profoundly decreased in pregnant mothers, which is thought to ensure adequate iron availability for transfer across placenta. However, the fetal liver also produces hepcidin, which may regulate fetal iron endowment by controlling placental iron export.
View Article and Find Full Text PDFAdequate iron supply during pregnancy is essential for fetal development. However, how fetal or amniotic fluid iron levels are regulated during healthy pregnancy, or pregnancies complicated by intraamniotic infection or inflammation (IAI), is unknown. We evaluated amniotic fluid and fetal iron homeostasis in normal and complicated murine, macaque, and human pregnancy.
View Article and Find Full Text PDFIron deficiency is common worldwide and is associated with adverse pregnancy outcomes. The increasing prevalence of indiscriminate iron supplementation during pregnancy also raises concerns about the potential adverse effects of iron excess. We examined how maternal iron status affects the delivery of iron to the placenta and fetus.
View Article and Find Full Text PDFTensor networks are powerful factorization techniques which reduce resource requirements for numerically simulating principal quantum many-body systems and algorithms. The computational complexity of a tensor network simulation depends on the tensor ranks and the order in which they are contracted. Unfortunately, computing optimal contraction sequences (orderings) in general is known to be a computationally difficult (NP-complete) task.
View Article and Find Full Text PDFDuring pregnancy, iron needs to increase substantially to support fetoplacental development and maternal adaptation to pregnancy. To meet these iron requirements, both dietary iron absorption and the mobilization of iron from stores increase, a mechanism that is in large part dependent on the iron-regulatory hormone hepcidin. In healthy human pregnancies, maternal hepcidin concentrations are suppressed in the second and third trimesters, thereby facilitating an increased supply of iron into the circulation.
View Article and Find Full Text PDF