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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].
Copper
Published in Judy A. Driskell, Ira Wolinsky, Sports Nutrition, 2005
Philip G. Reeves, W. Thomas Johnson
The metal iron (Fe) is a required nutrient in the diet of all mammals including humans, and Fe deficiency anemia is one of the world’s most prominent health problems. For the most part, the deficiency is caused by a low intake or low bioavailability of dietary Fe. However, other factors may be involved. For example, there is a direct link between the Cu status of individuals and their ability to absorb and utilize dietary Fe.62 It was known as early as the mid 19th century that Cu was associated with the cure of certain types of Fe-resistant anemia. In the early and mid 20th century, it was found through animal studies that dietary Fe or Fe injections would not prevent Cu deficiency-induced anemia in the rat model.63–65 It was then discovered that a Cu-dependent ferroxidase, Cp, was required to move Fe out of cells. However, not until the age of molecular biology, in the late 1990s and early 2000s, was it discovered that a Cu-dependent ferroxidase, hephaestin, similar to Cp resides in the enterocytes of the small intestine, aided the absorption of Fe from the diet.66–69 Thus, Cu affects Fe metabolism, and low Cu status can reduce Fe absorption and hamper Fe utilization in the body. Although most of the research so far has been done with animal models, it is likely that similar results will be found in humans. Because of these discoveries, it is recommended that no studies on iron requirements be attempted without first assuring that the Cu status of the study population is adequate. Individuals presenting with anemia that is unresponsive to iron therapy probably should have a Cu status assessment performed. Athletes are especially sensitive to the effects of anemia, because exercise performance depends on maximal efficiency of oxygen carrying capacity and oxygen utilization in the active muscles. As discussed later in this chapter, Cu along with Fe is closely involved in oxygen utilization.
Copper deficiency, a rare but correctable cause of pancytopenia: a review of literature
Published in Expert Review of Hematology, 2022
Nayha Tahir, Aqsa Ashraf, Syed Hamza Bin Waqar, Abdul Rafae, Leela Kantamneni, Taha Sheikh, Rafiullah Khan
Copper has a delicate homeostatic relationship with iron absorption and release to plasma. Hephaestin and ceruloplasmin are two essential copper-containing ferroxidase enzyme homologs affecting iron metabolism. Hephaestin is a GPI-anchored protein located in duodenal mucosa and oxidizes ferrous to ferric form, which is the absorbable form, released from ferroportin and then binding to apo-transferrin, entering the systemic circulation [48]. Copper deficiency leads to decreased hephaestin, thus decreased oxidation and release to systemic circuit, causing iron loss via gastrointestinal tract causing anemia through impaired hemoglobin production [10,48]. Ceruloplasmin is also essential for transferring iron from the monocyte–macrophage system to plasma, which can be hindered by supposed decreased ceruloplasmin production [49,50]. Ferroportin and divalent metal transporter (DMT1) located on the basolateral and apical membrane in enterocytes are upregulated to increase iron absorption as a compensatory effect [10,51]. This can also be shown by the upregulation of hypoxia-inducible factor 2 (HIF-2α), which also upregulates FPN, DMT1, and cytochrome b [52]. Additionally, copper also modulates ferrochelatase activity, which catalyzes the terminal step of heme synthesis by incorporating ferrous to protoporphyrin IX ring to form heme. Decreased copper, thus, leads to heme deficiency [53,54].
Hepcidin as a therapeutic target for anemia and inflammation associated with chronic kidney disease
Published in Expert Opinion on Therapeutic Targets, 2019
Jolanta Malyszko, Jacek S. Malyszko, Joanna Matuszkiewicz-Rowinska
Iron is the fourth most common element in the Earth’s crust and the most abundant transition redox-active metal in our body [2]. It has a dual property to either donate or to accept electrons, thereby it catalyzes many redox reactions in the cells. On one hand, it is essential for cell growth and survival, DNA synthesis, and repair, mitochondrial function, inflammation regulation, while on the other hand, it is also prerequisite for hemoglobin synthesis in erythrocytes [2]. Moreover, excess free iron is toxic to the cells due to its ability to catalyze free radical generation, oxidative stress, dysfunctional lipid membranes that ultimately leads to cell death and organ damage [2]. As systemic iron balance needs to be tightly regulated by the pathways that supply, utilize, recycle, and store iron thus specialized transport system and membrane carriers have evolved in humans to maintain iron in a soluble state that is suitable for circulation into the blood and transfer across cell membranes [3]. Iron homeostasis is modulating by highly sophisticated mechanisms including iron regulatory protein and hepcidin [4–6]. It relies mainly on the control of iron efflux from duodenal enterocytes and from recycling of senescent erythrocytes by macrophages through erythrophagocytosis. Heme catabolism takes place in macrophages where heme – oxygenase-1 release ferrous iron, together with carbon monoxide and bilirubin as byproducts [6]. Iron is either stored in intracellular ferritin or released out of the cells through ferroportin, the sole iron exporter. Hephaestin or ceruloplasmin oxidize released ferrous iron into ferric iron, which could be bound by transferrin and owing to transferrin-mediated uptake this iron is available for cell consumption [7–9].
Pathological mechanisms of abnormal iron metabolism and mitochondrial dysfunction in systemic lupus erythematosus
Published in Expert Review of Clinical Immunology, 2021
Chris Wincup, Natalie Sawford, Anisur Rahman
In the circulation, ferrous [Fe2+] iron is then oxidized to the ferric state [Fe3+] by the ferroxidase enzyme Ceruloplasmin [and the specialist enterocyte equivalent, Hephaestin], before it can then bind to transferrin, a soluble transporter protein predominantly produced by the liver that can bind two molecules of iron. When iron is bound to transferrin, it is known as holo-transferrin and when transferrin is not binding iron it is referred to as apo-transferrin. Once transported to a cell that requires iron to be taken up, transferrin binds to the cell surface transferrin receptor, which has a high affinity for holo-transferrin [41].