Dietary iron induces ferroportin 1 clustering and migration into the basolateral membrane of the rat intestinal epithelium

2001 ◽  
Vol 120 (5) ◽  
pp. A678-A678
Author(s):  
K YEH ◽  
M YEH ◽  
J GLASS
Keyword(s):  
Intestinal Epithelium ◽  
Basolateral Membrane ◽  
Dietary Iron ◽  
Ferroportin 1 ◽  
And Migration

scholarly journals Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis

2010 ◽  
Vol 64 (4) ◽  
pp. 281-286 ◽  
Author(s):  
Manuel Muñoz ◽  
José Antonio García-Erce ◽  
Ángel Francisco Remacha
Keyword(s):  
Iron Overload ◽  
Basolateral Membrane ◽  
Reticuloendothelial System ◽  
Target Cells ◽  
Apical Surface ◽  
Dietary Iron ◽  
Excess Iron ◽  
Hepatic Cells ◽  
Ferroportin 1 ◽  
Cellular Immune

Iron functionsIron is an essential micronutrient, as it is required for satisfactory erythropoietic function, oxidative metabolism and cellular immune response.Iron physiologyAbsorption of dietary iron (1–2 mg/day) is tightly regulated and just balanced against iron loss because there are no active iron excretory mechanisms. Dietary iron is found in haem (10%) and non-haem (ionic, 90%) forms, and their absorption occurs at the apical surface of duodenal enterocytes via different mechanisms. Iron is exported by ferroportin 1 (the only putative iron exporter) across the basolateral membrane of the enterocyte into the circulation (absorbed iron), where it binds to transferrin and is transported to sites of use and storage. Transferrin-bound iron enters target cells—mainly erythroid cells, but also immune and hepatic cells—via receptor-mediated endocytosis. Senescent erythrocytes are phagocytosed by reticuloendothelial system macrophages, haem is metabolised by haem oxygenase, and the released iron is stored as ferritin. Iron will be later exported from macrophages to transferrin. This internal turnover of iron is essential to meet the requirements of erythropoiesis (20–30 mg/day). As transferrin becomes saturated in iron-overload states, excess iron is transported to the liver, the other main storage organ for iron, carrying the risk of free radical formation and tissue damage.Regulation of iron homoeostasisHepcidin, synthesised by hepatocytes in response to iron concentrations, inflammation, hypoxia and erythropoiesis, is the main iron-regulatory hormone. It binds ferroportin on enterocytes, macrophages and hepatocytes triggering its internalisation and lysosomal degradation. Inappropriate hepcidin secretion may lead to either iron deficiency or iron overload.

scholarly journals Glycolipid-dependent and lectin-driven transcytosis in mouse enterocytes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Alena Ivashenka ◽  
Christian Wunder ◽  
Valerie Chambon ◽  
Roger Sandhoff ◽  
Richard Jennemann ◽  
...  
Keyword(s):  
Basolateral Membrane ◽  
Intestinal Barrier ◽  
Growth Factor Signaling ◽  
Dependent Manner ◽  
Galectin 3 ◽  
Cell Adhesion And Migration ◽  
Range Of Functions ◽  
Mouse Intestine ◽  
And Migration

AbstractGlycoproteins and glycolipids at the plasma membrane contribute to a range of functions from growth factor signaling to cell adhesion and migration. Glycoconjugates undergo endocytic trafficking. According to the glycolipid-lectin (GL-Lect) hypothesis, the construction of tubular endocytic pits is driven in a glycosphingolipid-dependent manner by sugar-binding proteins of the galectin family. Here, we provide evidence for a function of the GL-Lect mechanism in transcytosis across enterocytes in the mouse intestine. We show that galectin-3 (Gal3) and its newly identified binding partner lactotransferrin are transported in a glycosphingolipid-dependent manner from the apical to the basolateral membrane. Transcytosis of lactotransferrin is perturbed in Gal3 knockout mice and can be rescued by exogenous Gal3. Inside enterocytes, Gal3 is localized to hallmark structures of the GL-Lect mechanism, termed clathrin-independent carriers. These data pioneer the existence of GL-Lect endocytosis in vivo and strongly suggest that polarized trafficking across the intestinal barrier relies on this mechanism.

Apical location of ferroportin 1 in airway epithelia and its role in iron detoxification in the lung

2005 ◽  
Vol 289 (1) ◽  
pp. L14-L23 ◽  
Author(s):  
Funmei Yang ◽  
David J. Haile ◽  
Xinchao Wang ◽  
Lisa A. Dailey ◽  
Jacqueline G. Stonehuerner ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Iron Homeostasis ◽  
Imaging Techniques ◽  
Basolateral Membrane ◽  
Airway Epithelial Cells ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Ferroportin 1 ◽  
Immunofluorescence Labeling

Ferroportin 1 (FPN1; aka MTP1, IREG1, and SLC40A1), which was originally identified as a basolateral iron transporter crucial for nutritional iron absorption in the intestine, is expressed in airway epithelia and upregulated when these cells are exposed to iron. Using immunofluorescence labeling and confocal microscopic imaging techniques, we demonstrate that in human and rodent lungs, FPN1 localizes subcellularly to the apical but not basolateral membrane of the airway epithelial cells. The role of airway epithelial cells in iron mobilization in the lung was studied in an in vitro model of the polarized airway epithelium. Normal human bronchial epithelial cells, grown on membrane supports until differentiated, were exposed to iron, and the efficiency and direction of iron transportation were studied. We found that these cells can efficiently take up iron across the apical but not basolateral surface in a concentration-dependent manner. Most of the iron taken up by the cells is then released into the medium within 8 h in the form of less reactive protein-bound complexes including ferritin and transferrin. Interestingly, iron release also occurred across the apical but not basolateral membrane. Our findings indicate that FPN1, depending on its subcellular location, could have distinct functions in iron homeostasis in different cells and tissues. Although it is responsible for exporting nutrient iron from enterocytes to the circulation in the intestine, it could play a role in iron detoxification in airway epithelial cells in the lung.

scholarly journals Defective Slc7a7 transport reduces systemic arginine availability compromising erythropoiesis and iron homeostasis

2021 ◽  
Author(s):  
Fernando Sotillo ◽  
Judith Giroud-Gerbetant ◽  
Jorge Couso ◽  
Rafael Artuch ◽  
Antonio Zorzano ◽  
...  
Keyword(s):  
Amino Acid ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Basolateral Membrane ◽  
M Cell ◽  
Cationic Amino Acid ◽  
Ferroportin 1 ◽  
Lysinuric Protein ◽  
Wide Variability

Slc7a7 encodes for y+LAT1, a transporter of cationic amino acid across the basolateral membrane of epithelial cells. Mutations in SLC7A7 gene give rise to Lysinuric Protein Intolerance (LPI), a rare autosomal recessive disease with wide variability of complications. Intriguingly, y+LAT1 is also involved in arginine transport in non polarized cells such as macrophages. Here we report that complete inducible Slc7a7 ablation in mouse compromises systemic arginine availability that alters proper erythropoiesis and that dysfunctional RBC generation leads to increased erythrophagocytosis, iron overload and an altered iron metabolism by macrophages. Herein, uncovering a novel mechanism that links amino acid metabolism to erythropoiesis and iron metabolism. Mechanistically, the iron exporter ferroportin-1 expression was compromised by increased plasma hepcidin causing macrophage iron accumulation. Strikingly, lysozyme M-cell-specific knockout mice failed to reproduce the total knockout alterations, while bone marrow transplantation experiments resulted in the resolution of macrophage iron overload but could not overcome erythropoietic defect. This study establishes a new crucial link between systemic arginine availability in erythropoiesis and iron homeostasis.

scholarly journals Iron feeding induces ferroportin 1 and hephaestin migration and interaction in rat duodenal epithelium

2009 ◽  
Vol 296 (1) ◽  
pp. G55-G65 ◽  
Author(s):  
Kwo-yih Yeh ◽  
Mary Yeh ◽  
Laura Mims ◽  
Jonathan Glass
Keyword(s):  
Brush Border Membrane ◽  
Iron Absorption ◽  
Basolateral Membrane ◽  
Hek293 Cells ◽  
Velocity Sedimentation ◽  
Cell Sheets ◽  
Ferroportin 1 ◽  
Sds Page ◽  
Duodenal Epithelium ◽  
Blue Native

Intestinal iron absorption involves proteins located in the brush border membrane (BBM), cytoplasm, and basolateral membrane (BLM) of duodenal enterocytes. Ferroportin 1 (FPN1) and hephaestin (Heph) are necessary for transport of iron out of enterocytes, but it is not known whether these two proteins interact during iron absorption. We first examined colocalization of the proteins by cotransfection of HEK293 cells with pDsRed-FPN1 with pEmGFP-Heph or with the COOH-terminal truncated pEmGFP-HephΔ43 or -HephΔ685 and found that FPN1 and Heph with or without the COOH terminus colocalized. In rat duodenal enterocytes, within 1 h of iron feeding prominent migration of FPN1 from the apical subterminal zone to the basal subnuclear zone of the BLM occurred and increased to at least 4 h after feeding. Heph exhibited a similar though less prominent migration after iron ingestion. Analysis using rat duodenal epithelial cell sheets demonstrated that 1) by velocity sedimentation ultracentrifugation, FPN1 and Heph occupied vesicles of different sizes prior to iron feeding and migrated to similar fractions 1 h after iron feeding; 2) by blue native/SDS-PAGE, FPN1, and Heph interacted to form two complexes, one containing dimeric FPN1 and intact Heph and the other consisting of monomeric FPN1 and a Heph fragment; and 3) by immunoprecipitation, anti-Heph or anti-FPN1 antiserum coimmunoprecipitated FPN1 and Heph. Thus the data indicate that FPN1 and Heph migrate and interact during iron feeding and suggest that dimeric FPN1 is associated with intact Heph.

Cellular and Subcellular Localization of the Nramp2 Iron Transporter in the Intestinal Brush Border and Regulation by Dietary Iron

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4406-4417 ◽  
Author(s):  
F. Canonne-Hergaux ◽  
S. Gruenheid ◽  
P. Ponka ◽  
P. Gros
Keyword(s):  
Small Intestine ◽  
Subcellular Localization ◽  
Brush Border ◽  
Iron Acquisition ◽  
Basolateral Membrane ◽  
Microcytic Anemia ◽  
The Body ◽  
Protein Isoforms ◽  
Dietary Iron ◽  
Iron Starvation

Abstract Genetic studies in animal models of microcytic anemia and biochemical studies of transport have implicated the Nramp2gene in iron transport. Nramp2 generates two alternatively spliced mRNAs that differ at their 3′ untranslated region by the presence or absence of an iron-response element (IRE) and that encode two proteins with distinct carboxy termini. Antisera raised against Nramp2 fusion proteins containing either the carboxy or amino termini of Nramp2 and that can help distinguish between the two Nramp2 protein isoforms (IRE: isoform I; non-IRE: isoform II) were generated. These antibodies were used to identify the cellular and subcellular localization of Nramp2 in normal tissues and to study possible regulation by dietary iron deprivation. Immunoblotting experiments with membrane fractions from intact organs show that Nramp2 is expressed at low levels throughout the small intestine and to a higher extent in kidney. Dietary iron starvation results in a dramatic upregulation of the Nramp2 isoform I in the proximal portion of the duodenum only, whereas expression in the rest of the small intestine and in kidney remains largely unchanged in response to the lack of dietary iron. In proximal duodenum, immunostaining studies of tissue sections show that Nramp2 protein expression is abundant under iron deplete condition and limited to the villi and is absent in the crypts. In the villi, staining is limited to the columnar absorptive epithelium of the mucosa (enterocytes), with no expression in mucus-secreting goblet cells or in the lamina propria. Nramp2 expression is strongest in the apical two thirds of the villi and is very intense at the brush border of the apical pole of the enterocytes, whereas the basolateral membrane of these cells is negative for Nramp2. These results strongly suggest that Nramp2 is indeed responsible for transferrin-independent iron uptake in the duodenum. These findings are discussed in the context of overall mechanisms of iron acquisition by the body.

scholarly journals Shigella flexneri Interactions with the Basolateral Membrane Domain of Polarized Model Intestinal Epithelium: Role of Lipopolysaccharide in Cell Invasion and in Activation of the Mitogen-Activated Protein Kinase ERK

2002 ◽  
Vol 70 (3) ◽  
pp. 1150-1158 ◽  
Author(s):  
Henrik Köhler ◽  
Sonia P. Rodrigues ◽  
Beth A. McCormick
Keyword(s):  
Protein Kinase ◽  
Intestinal Epithelium ◽  
Shigella Flexneri ◽  
Basolateral Membrane ◽  
Mitogen Activated Protein Kinase ◽  
Mucosal Inflammation ◽  
Initial Contact ◽  
Wild Type ◽  
Membrane Domain ◽  
Mitogen Activated Protein

ABSTRACT An early step governing Shigella flexneri pathogenesis is the invasion of the colonic epithelium from the basolateral surface followed by disruption of the colonic epithelial barrier. Despite recent insight into S. flexneri-host interactions, much remains to be determined regarding the nature of the initial contact between S. flexneri and the host epithelial basolateral membrane domain. Since the lipopolysaccharide (LPS) is located at the outermost part of the bacterial membrane, we considered that this component might be used by S. flexneri to attach to the basolateral surface of the intestinal epithelium and promote a proinflammatory response. Therefore, polarized human T84 intestinal epithelial cells were infected from the basolateral surface with either wild-type S. flexneri or one of its isogenic LPS-defective strains with mutations in either rfc, rfaL, or galU. We found that both adherence to and internalization into the basolateral surface of a polarized intestinal epithelium with S. flexneri were highly dependent on the length of the LPS (i.e., rfc > rfaL > galU). Furthermore, the addition of the anti-inflammatory LPS (RsDPLA) considerably decreased the invasion profile of wild-type S. flexneri by nearly 50%. Since LPS is associated with host inflammation, we further examined whether this molecule was involved in Shigella-induced inflammatory events. We found that S. flexneri LPS plays an important role in mediating epithelial-derived signaling, which leads to directed migration of polymorphonuclear leukocytes across model intestinal epithelium. This signaling most likely involves the activation of the mitogen-activated protein kinase extracellular regulated kinase. Thus, our findings have important implications on the understanding of the mechanisms by which S. flexneri can elicit mucosal inflammation.

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