984 Suppression of LPS and IL-6 Signaling By Iron Deficiency Alters Expression of the Intestinal Iron Absorption Regulator Hepcidin

2008 ◽  
Vol 134 (4) ◽  
pp. A-147
Author(s):  
Deepak Darshan ◽  
David M. Frazer ◽  
Sarah J. Wilkins ◽  
Gregory J. Anderson
Keyword(s):  
Iron Deficiency ◽  
Iron Absorption ◽  
Intestinal Iron Absorption

Decreased mucosal iron induces an increase in intestinal iron absorption in the early stage of iron-deficiency

2000 ◽  
Vol 20 (10) ◽  
pp. 1457-1465
Author(s):  
Toshio Mikami ◽  
Sanae Hisayasu ◽  
Yuki Ikeda-More ◽  
Yoshio Yoshino
Keyword(s):  
Iron Deficiency ◽  
Iron Absorption ◽  
Early Stage ◽  
Intestinal Iron Absorption

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.

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 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.

Effect of Soluble Fiber Pectin on Growth and Intestinal Iron Absorption in Rats During Recovery from Iron Deficiency Anemia

2009 ◽  
Vol 129 (1-3) ◽  
pp. 221-228 ◽  
Author(s):  
Carolina Feltrin ◽  
Mauro Batista de Morais ◽  
Karine de Cássia Freitas ◽  
Tânia Beninga de Morais ◽  
Ulysses Fagundes Neto ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Absorption ◽  
Deficiency Anemia ◽  
Soluble Fiber ◽  
Intestinal Iron Absorption

The relative importance of luminal and systemic signals in the control of intestinal iron absorption

2001 ◽  
Vol 120 (5) ◽  
pp. A678-A679
Author(s):  
G ANDERSON ◽  
S WILKINS ◽  
T MURPHY ◽  
G CLEGHORN ◽  
D FRAZER
Keyword(s):  
Iron Absorption ◽  
Relative Importance ◽  
Intestinal Iron Absorption ◽  
Systemic Signals
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