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The Contribution of Iron and Transition Metal Micronutrients to Diabetes and Metabolic Disease
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Lipika Salaye, Zhenzhong Bai, Donald A. McClain
Systemic and cellular iron metabolism have been the subject of excellent recent reviews [9–11] and will be only briefly recapitulated here (Figure 15.1). Intestinal free ferric (Fe3+) iron is reduced to ferrous Fe2+ by duodenal cytochrome B (DCTB) and enters duodenal enterocytes by way of the divalent metal-ion transporter 1 (DMT1) and possibly other carriers. Dietary heme is directly absorbed into enterocytes, where iron is released by heme oxygenase (HMOX). Ferrous iron exits the enterocytes through the iron export channel ferroportin (FPN). After oxidization by hephaestin (HEPH), Fe3+ binds to transferrin (Tf) in the blood, which in turn binds to transferrin receptors (TfR) on the surface of target cells. In most cells (Figure 15.1, lower right), after endocytosis of TfR1 and acidification of the endosome, iron is released, reduced by STEAP (6-transmembrane epithelial antigen of the prostate), and enters the cytosol through DMT1, where it is used (e.g., for heme or Fe-S-cluster synthesis in mitochondria) or, if in excess, sequestered by ferritin. Apoferritin secreted into the circulation is a marker for tissue iron stores, although the trigger for its secretion versus use to sequester more iron is not known. The intracellular trafficking of iron is much more complicated than indicated in the figure. For example, iron is highly controlled and chaperoned to its various targets, as ferrous iron or after iron-sulfur cluster synthesis, by mechanisms that are still under study [6].
Ferumoxytol: an emerging therapeutic for iron deficiency anemia
Published in Expert Opinion on Pharmacotherapy, 2023
Midori Sakashita, Masaomi Nangaku
Most of the dietary iron is absorbed from the duodenum, with non-heme iron being absorbed by the intestinal epithelial cells via duodenal cytochrome B (DYCTB) and heme iron via the heme carrier protein (HCP1). Intracellular iron is also absorbed into the blood via ferroportin present on the basement membrane. This free iron is transported in the blood by transferrin, and the excess iron accumulates as ferritin and hemosiderin, which are types of stored iron. Most of the stored iron is present in the macrophages of the liver, spleen, and bone marrow. Iron absorption is tightly regulated by hepcidin and hypoxia-inducible factor (HIF). Hepcidin is a protein produced by the liver that is elevated during the acute phase of inflammation. Hepcidin internalizes or degrades ferroportin, the only protein that pumps iron out of the cells, reducing the amount of available iron [7,8].
A novel treatment strategy to prevent Parkinson’s disease: focus on iron regulatory protein 1 (IRP1)
Published in International Journal of Neuroscience, 2023
Thomas M. Berry, Ahmed A. Moustafa
Hypoxia-inducible factor-2 alpha (HIF2α) mRNA transcripts have a 5′ iron-responsive element whereby HIF2α mRNA transcripts are destabilized by IRP1 [79]. The transcription of ferroportin is induced by HIF2α [80]. HIF2α induces transcription of duodenal cytochrome b reductase (DCYTB) which is a ferric reductase involved in iron absorption [79]. HIF2α also induces transcription of the gene for DMT1 [81]. High activity of IRP1 in PD in the gut by decreasing translation of HIF2α will decrease transcription of ferroportin, decrease transcription of DMT1 and decrease transcription of duodenal cytochrome b reductase in the gut all of which could contribute to a systematic loss of control over iron utilization.
Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease
Published in Expert Opinion on Investigational Drugs, 2018
Lucia Del Vecchio, Francesco Locatelli
Given that iron is essential for erythropoiesis and is the second important constituent for PHD activity, it is no surprise that the HIF system has a significant role in the regulation of iron metabolism. Indeed, it orchestrates the expression of the genes encoding the molecules involved in intestinal iron uptake: duodenal cytochrome b, apical divalent metal transporter [39], and ferroportin [40]. Moreover, it stimulates the synthesis of transferrin [41], its receptor [42], and ferrochelatase, the enzyme that catalyzes the insertion of iron into protoporphyrin to form heme [43].