scholarly journals Intestinal ferritinophagy is regulated by HIF-2α and is essential for systemic iron homeostasis

2020 ◽  
Author(s):  
Nupur K Das ◽  
Amanda Sankar ◽  
Andrew J Schwartz ◽  
Sumeet Solanki ◽  
Xiaoya Ma ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Whole Body ◽  
Null Mouse ◽  
Divalent Metal Transporter 1 ◽  
Intestinal Iron Absorption ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Iron Sequestration

AbstractIron is critical for many processes including oxygen transport and erythropoiesis. Transcriptomic analysis demonstrates that HIF-2α regulates over 90% of all transcripts induced following iron deficiency in the intestine. However, beyond divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1) and duodenal cytochrome b (Dcytb), no other genes/pathways have been critically assessed with respects to their importance in intestinal iron absorption. Ferritinophagy is associated with cargo specific autophagic breakdown of ferritin and subsequent release of iron. We show here that nuclear receptor co-activator 4 (NCOA4)-mediated intestinal ferritinophagy is integrated to systemic iron demand via HIF-2α. Duodenal NCOA4 expression is regulated by HIF-2α during high systemic iron demands. Moreover, overexpression of intestinal HIF-2α is sufficient to activate NCOA4 and promote lysosomal degradation of ferritin. Promoter analysis revealed NCOA4 as a direct HIF-2α target. To demonstrate the importance of intestinal HIF-2α/ferritinophagy axis in systemic iron homeostasis, whole body and intestine-specific NCOA4-null mouse lines were assessed. These analyses demonstrate an iron sequestration in the enterocytes, and significantly high tissue ferritin levels in the dietary iron deficiency and acute hemolytic anemia models. Together, our data suggests efficient ferritinophagy is critical for intestinal iron absorption and systemic iron homeostasis.

Modulation of the HIF2-NCOA4 axis in enterocytes attenuates iron loading in a mouse model of hemochromatosis

Blood ◽  
2022 ◽  
Author(s):  
Nupur K Das ◽  
Chesta Jain ◽  
Amanda D. Sankar ◽  
Andrew J Schwartz ◽  
Naiara Santana-Codina ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Mouse Model ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Hypoxia Inducible Factor ◽  
Whole Body ◽  
Deficiency Anemia ◽  
Null Mouse ◽  
Intestinal Iron Absorption

Intestinal iron absorption is activated during increased systemic iron demand. The best-studied example is iron-deficiency anemia, which increases intestinal iron absorption. Interestingly, the intestinal response to anemia is very similar to that of iron overload disorders, as both the conditions activate a transcriptional program that leads to a hyperabsorption of iron via the transcription factor hypoxia-inducible factor (HIF)2a. However, pathways to selectively target intestinal-mediated iron overload remain unknown. Nuclear receptor co-activator 4 (NCOA4) is a critical cargo receptor for autophagic breakdown of ferritin (FTN) and subsequent release of iron, in a process termed ferritinophagy. Our work demonstrates that NCOA4-mediated intestinal ferritinophagy is integrated to systemic iron demand via HIF2a. To demonstrate the importance of intestinal HIF2a/ferritinophagy axis in systemic iron homeostasis, whole body and intestine-specific NCOA4-null mouse lines were generated and assessed. These analyses revealed that the intestinal and systemic response to iron deficiency was not altered following disruption of intestinal NCOA4. However, in a mouse model of hemochromatosis, ablation of intestinal NCOA4 was protective against iron overload. Therefore, NCOA4 can be selectively targeted for the management of iron overload disorders without disrupting the physiological processes involved in the response to systemic iron deficiency.

scholarly journals Mechanistic and regulatory aspects of intestinal iron absorption

2014 ◽  
Vol 307 (4) ◽  
pp. G397-G409 ◽  
Author(s):  
Sukru Gulec ◽  
Gregory J. Anderson ◽  
James F. Collins
Keyword(s):  
Iron Homeostasis ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Regulatory Protein ◽  
Whole Body ◽  
Deficiency Anemia ◽  
Inherited Disorders ◽  
Intestinal Iron Absorption ◽  
Body Iron ◽  
Proximal Small Bowel

Iron is an essential trace mineral that plays a number of important physiological roles in humans, including oxygen transport, energy metabolism, and neurotransmitter synthesis. Iron absorption by the proximal small bowel is a critical checkpoint in the maintenance of whole-body iron levels since, unlike most other essential nutrients, no regulated excretory systems exist for iron in humans. Maintaining proper iron levels is critical to avoid the adverse physiological consequences of either low or high tissue iron concentrations, as commonly occurs in iron-deficiency anemia and hereditary hemochromatosis, respectively. Exquisite regulatory mechanisms have thus evolved to modulate how much iron is acquired from the diet. Systemic sensing of iron levels is accomplished by a network of molecules that regulate transcription of the HAMP gene in hepatocytes, thus modulating levels of the serum-borne, iron-regulatory hormone hepcidin. Hepcidin decreases intestinal iron absorption by binding to the iron exporter ferroportin 1 on the basolateral surface of duodenal enterocytes, causing its internalization and degradation. Mucosal regulation of iron transport also occurs during low-iron states, via transcriptional (by hypoxia-inducible factor 2α) and posttranscriptional (by the iron-sensing iron-regulatory protein/iron-responsive element system) mechanisms. Recent studies demonstrated that these regulatory loops function in tandem to control expression or activity of key modulators of iron homeostasis. In health, body iron levels are maintained at appropriate levels; however, in several inherited disorders and in other pathophysiological states, iron sensing is perturbed and intestinal iron absorption is dysregulated. The iron-related phenotypes of these diseases exemplify the necessity of precisely regulating iron absorption to meet body demands.

scholarly journals Increased DMT1 and FPN1 expression with enhanced iron absorption in ulcerative colitis human colon

2020 ◽  
Vol 318 (2) ◽  
pp. C263-C271 ◽  
Author(s):  
Emily A. Minor ◽  
Justin T. Kupec ◽  
Andrew J. Nickerson ◽  
Karthikeyan Narayanan ◽  
Vazhaikkurichi M. Rajendran
Keyword(s):  
Ulcerative Colitis ◽  
Iron Deficiency ◽  
Iron Absorption ◽  
Basolateral Membrane ◽  
Specific Inhibitor ◽  
Distal Colon ◽  
Human Colon ◽  
Deficiency Anemia ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter

Iron deficiency anemia is a common complication of ulcerative colitis (UC) that can profoundly impact quality of life. Most iron absorption occurs in the duodenum via divalent metal transporter 1 (DMT1)-mediated uptake and ferroportin-1 (FPN1)-mediated export across the apical and basolateral membranes, respectively. However, the colon also contains iron transporters and can participate in iron absorption. Studies have shown increased duodenal DMT1 and FPN1 in patients with UC, but there is conflicting evidence about whether expression is altered in UC colon. We hypothesized that expression of colonic DMT1 and FPN1 will also increase to compensate for iron deficiency. Quantitative RT-PCR and Western blot analyses were performed on duodenal and colonic segmental (right colon, transverse colon, left colon, and rectum) biopsies obtained during colonoscopy. DMT1 mRNA and protein abundances in colonic segments were approximately equal to those in the duodenum, whereas colonic FPN1 mRNA and protein abundances of colonic segments were about one-quarter of those of the duodenum. DMT1 specific mRNA and protein abundances were increased twofold, whereas FPN1 mRNA and protein expressions were increased fivefold in UC distal colon. Immunofluorescence studies revealed enhanced expression of apical membrane- and basolateral membrane-localized DMT1 and FPN1 in UC human colon, respectively. Increased DMT1 expression was associated with enhanced 2-(3-carbamimidoylsulfanylmethyl-benzyl)-isothiourea (CISMBI, DMT1 specific inhibitor)-sensitive 59Fe uptake in UC human colon. We conclude from these results that patients with active UC have increased expression of colonic iron transporters and increased iron absorption, which may be targeted in the treatment of UC-related anemia.

Relationship between intestinal iron-transporter expression, hepatic hepcidin levels and the control of iron absorption

2002 ◽  
Vol 30 (4) ◽  
pp. 724-726 ◽  
Author(s):  
G.J. Anderson ◽  
D. M. Frazer ◽  
S.J. Wilkins ◽  
E. M. Becker ◽  
K. N. Millard ◽  
...  
Keyword(s):  
Iron Transport ◽  
Iron Absorption ◽  
Negative Regulator ◽  
Deficient Diet ◽  
Divalent Metal Transporter 1 ◽  
Intestinal Iron Absorption ◽  
Divalent Metal Transporter ◽  
Hepcidin Expression ◽  
Iron Deficient ◽  
Transport Molecules

Hepcidin is an anti-microbial peptide predicted to be involved in the regulation of intestinal iron absorption. We have examined the relationship between the expression of hepcidin in the liver and the expression of the iron-transport molecules divalent-metal transporter 1, duodenal cytochrome b, hephaestin and Ireg1 in the duodenum of rats switched from an iron-replete to an iron-deficient diet or treated to induce an acute phase response. In each case, elevated hepcidin expression correlated with reduced iron absorption and depressed levels of iron-transport molecules. These data are consistent with hepcidin playing a role as a negative regulator of intestinal iron absorption.

Iron supply determines apical/basolateral membrane distribution of intestinal iron transporters DMT1 and ferroportin 1

2010 ◽  
Vol 298 (3) ◽  
pp. C477-C485 ◽  
Author(s):  
Marco T. Núñez ◽  
Victoria Tapia ◽  
Alejandro Rojas ◽  
Pabla Aguirre ◽  
Francisco Gómez ◽  
...  
Keyword(s):  
Translational Regulation ◽  
Fluorescent Protein ◽  
Iron Absorption ◽  
Iron Status ◽  
Basolateral Membrane ◽  
Membrane Domains ◽  
Divalent Metal Transporter 1 ◽  
Intestinal Iron Absorption ◽  
Divalent Metal Transporter ◽  
Iron Supply

Intestinal iron absorption comprises the coordinated activity of the influx transporter divalent metal transporter 1 (DMT1) and the efflux transporter ferroportin (FPN). In this work, we studied the movement of DMT1 and FPN between cellular compartments as a function of iron supply. In rat duodenum, iron gavage resulted in the relocation of DMT1 to basal domains and the internalization of basolateral FPN. Considerable FPN was also found in apical domains. In Caco-2 cells, the apical-to-basal movement of cyan fluorescent protein-tagged DMT1 was complete 90 min after the addition of iron. Steady-state membrane localization studies in Caco-2 cells revealed that iron status determined the apical/basolateral membrane distribution of DMT1 and FPN. In agreement with the membrane distribution of the transporters,55Fe flux experiments revealed inward and outward iron fluxes at both membrane domains. Antisense oligonucleotides targeted to DMT1 or FPN inhibited basolateral iron uptake and apical iron efflux, respectively, indicating the participation of DMT1 and FPN in these fluxes. The fluxes were regulated by the iron supply; increased iron reduced apical uptake and basal efflux and increased basal uptake and apical efflux. These findings suggest a novel mechanism of regulation of intestinal iron absorption based on inward and outward fluxes at both membrane domains, and repositioning of DMT1 and FPN between membrane and intracellular compartments as a function of iron supply. This mechanism should be complementary to those based in the transcriptional or translational regulation of iron transport proteins.

The Gut: Role at Steady State and Variations in Disordered Conditions

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-23-SCI-23
Author(s):  
Carole Peyssonnaux
Keyword(s):  
Iron Deficiency ◽  
Intestinal Epithelium ◽  
Iron Absorption ◽  
Genetic Disorder ◽  
Iron Concentration ◽  
Conditional Knockout ◽  
Divalent Metal Transporter 1 ◽  
Α Subunit ◽  
Intestinal Iron Absorption ◽  
Body Iron

Abstract Abstract SCI-23 As the human body cannot excrete excess iron, its absorption needs to be finely regulated at the intestinal level. Ferric iron (Fe3+) is reduced to ferrous iron (Fe2+) by brush border ferric reductases, including duodenal cytochrome b (DCYTB), before being transported across the apical membrane by divalent metal transporter 1 (DMT1), which is the principal iron importer. Depending on body iron requirements, iron can be either stored bound to ferritin or exported across the basolateral enterocyte membrane into the plasma by the sole iron exporter ferroportin (FPN). Iron absorption responds to systemic signals reflecting body iron requirements and local signals in the enterocyte. At the systemic level, hepcidin is the key circulating peptide hormone maintaining iron homeostasis. Hepcidin controls plasma iron concentration by inhibiting intestinal iron absorption and iron recycling by macrophages. Hepcidin acts by inhibiting cellular iron efflux through binding to and inducing the degradation of FPN. Hepcidin transcription is upregulated by iron repletion and downregulated by iron deficiency, ineffective erythropoiesis, and hypoxia. Hypoxia-inducible factors HIF-1 and HIF-2 are heterodimeric transcriptional factors and central mediators of cellular and systemic adaptation to hypoxia. In the presence of oxygen, the HIF-α subunit is targeted to the proteasome, while in hypoxia (or iron deficiency), HIF-α is stabilized and induces the transcription of target genes. We hypothesized that HIFs, stabilized in the hypoxic intestinal epithelium, may also play critical local roles in regulating intestinal iron absorption. We generated conditional knockout mice that lacked either Hif1a or Hif2a specifically in the intestinal epithelium and found that HIF-1α was not necessary for iron absorption, whereas HIF-2α played a crucial role in maintaining iron balance in the organism by directly regulating the transcription of the genes encoding DMT1 and DCYTB. Specific deletion of Hif2a led to a decrease in serum and liver iron levels. Alterations in HIF-2 at the intestinal level can override systemic regulation via hepcidin. Interestingly, we further demonstrated that HIF-2α contributes to iron hyperabsorption in a genetic mouse model of hereditary hemochromatosis (HH). HH is a genetic disorder characterized by abnormally low hepcidin expression and excessive iron accumulation in the liver and parenchyma. These findings suggest a prominent role of HIF-2 in the physiopathological regulation of intestinal iron absorption and may provide new therapeutic perspectives for the treatment of anemias and iron overload-associated disorders. Disclosures: No relevant conflicts of interest to declare.

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