Iron Part 2: Anaemia Flashcards

Question

Which proteins in the small intestine are used for regulation of Iron?

Answer 1

**Ferroreductase** * Reduces dietary Fe3+ to Fe2+ for absorption. Acidic pH effluent **Divalent metal transporter 1 (DMT1)** * Proton-coupled transport of Fe2+ across apical membrane * Increased in iron deficiency due to increased responsivity to intracellular labile iron pool. Due to increased gene expression and altered mRNA processing * Can also be used to transport Mn2+, Zn2+, Co2+, Cd2+, Pb2+ * Haem iron absorbed separately by efficient receptor-mediated endocytosis **Ferroportin** * Transports iron across basolateral membrane into circulation

Answer 2

**Ferritin-bound iron is lost via enterocyte senescence. Ferroportin is responsible for basolateral iron transport:** * Ferroportin activity is regulated via hepcidin * Decreased activity in presence of high iron * Ferroportin transcription is regulated via free iron pool * Increased protein synthesis in presence of high iron

Answer 3

* **Transferrin Receptor:** Accepts delivery of transferrin-bound iron via transferrin cycle * **DMT1:** Transports iron out of endosomes

Answer 4

* 190 kDA: 2x 95 kDa subunits joined by S-S bond * High affinity for diferric and monomeric transferrin at neutral pH * High affinity of apo-transferrin at acidic pH * Soluble transferrin receptor is a truncated monomer of the tissue receptor that circulates in a complex with transferrin * Classical transferrin receptor (TFR1) in all tissues. It is highly expressed on rapidly dividing cells and increased expression in iron deficiency

Answer 5

* Erythropoiesis uses major portion of body iron to produce new RBCs * Controlled by the stromal network, cytokines and erythropoietin * Reticulocytes generated in the bone marrow are released after 3 days. After 1 day in the circulation, reticulocytes lose their ribosomal network and become mature RBCs * At steady state, rate of RBC production equals rate of loss

Answer 6

* Apotransferrin’ binds Fe3+ at the basolateral surface of enterocytes * Transferrin delivers iron to cells expressing transferrin receptors * TFR1 selectively binds diferric ‘holotransferrin’. This leads to membrane invagination forming endosomes. * H+ influx causes release of HCO3- and Fe3+ from transferrin. Apotransferrin dissociates from TFR1 * Liberated Fe3+ is reduced to Fe2+ by STEAP3 ferrireducatase * DMT1 transports Fe2+ into the cytoplasm of the recipient cell

Answer 7

HFE competes with holotransferrin for binding to TFR1 * Increased iron bioavailability increases saturation of transferrin. * More holotransferrin is available to bind TFR1. HFE is released High labile iron pool increases HFE expression (reciprocally to DMT1

Answer 8

* **Ferroportin:** Transports stored iron out of hepatocytes into circulation * **BMP6** * **HFE:** Regulates supply of hepcidin in response to iron * **Ferritin:** Hepatocyte iron storage protein

Answer 9

Regulated By Paracrine Signaling * Intercellular crosstalk between different liver cells * Hepcidin is positively regulated by plasma holotransferrin, hepatic iron stores and inflammation * Iron stores sensed by hepatic sinusoidal endothelial cells: ↑ BMP6 * Hepcidin transcription upregulated by haemojuvelin, HFE and TFR2 * Holotransferrin may upregulate hepcidin regulation via release of HFE from TFR1 and increased binding of HFE to TFR2 Hepcidin synthesis is negatively regulated by increased erythropoiesis and hypoxia

Answer 10

* Hepatic endothelial cells produce BMP6, which binds to the BMP receptors (BMPR) and BMP coreceptor hemojuvelin (HJV) on the hepatocyte cell membrane, activating the BMP-SMAD pathway and inducing hepcidin expression. * This can be inhibited by matriptase 2 (MT-2), which cleaves HJV. * Hepatic macrophages produce inflammatory cytokines, including IL-6, in response to antigens and infectious agents. IL-6 binds to IL-6 receptors on the hepatocyte membrane, activating the JAK-STAT pathway and inducing hepcidin expression.

Answer 11

* **Ferroportin:** Transports recycled iron out of macrophages for transferrin uptake * **Ferritin:** Excess iron stored in macrophages

Answer 12

RBCs ingested by macrophages after 120 days * Macrophages release Fe2+ via ferroportin * Fe2+ oxidised to Fe3+ by membrane-bound iron oxidase, allowing uptake and delivery by transferrin Cytosolic Fe3+ reduced to Fe2+ for uptake into iron core, re-oxidised to Fe3+, stored as ferric oxyhydroxide phosphate 750-2000 mg iron stored in health * Ferritin & haemosiderin * 1/3 each in liver, macrophages & bone marrow * Lysosomes turn over iron pool every few days

Answer 13

* Cytoplasmic iron response proteins (IRPs) sense concentration of chelatable iron in the labile pool * IRP1 forms an 4Fe-4S cluster when iron is abundant (clusters cannot bind mRNA) * IRP2 degradation is triggered by high iron concentration (not available to bind mRNA)

Answer 14

Translational regulation * mRNA is synthesised by transcription from DNA * Proteins are synthesised by translation of mRNA * Initiation of protein synthesis requires binding of large cellular enzyme apparatus to the 5’ untranslated region (UTR) of mRNA * Synthesis of a complete amino acid chain requires progression of the translational apparatus though to the 3’ UTR of the mRNA Iron regulatory Proteins bind to hairpin iron response elements (IREs) in mRNA, sterically altering translation and affecting mRNA stability Increased translation: proteins with IRE in 5’UTR of mRNA, so in presence of high iron there are no functional IRPs to block binding of translational apparatus * H- and L-ferritin * Ferroportin * ALA synthase (haem synthesis) Decreased translation: proteins with IRE in 3’UTR of mRNA, so in presence of high iron no functional IRPs to stabilise mRNA: DMT1, TFR1

Iron Part 2: Anaemia Flashcards

(38 cards)