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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
The liver is one of the primary organs that regulates systemic iron balance. In the liver, Tf binds TfR2 and the protein HFE, and in concert with signaling via the glycophosphatidylinositol (GPI)-anchored protein hemojuvelin (HJV), bone morphogenic proteins (BMPs), and transducers of TGFβ signaling (SMAD’s), the 21mer peptide hepcidin is produced. Hepcidin induces internalization and degradation of FPN in the enterocytes, thus completing a negative feedback regulatory loop. Hepcidin and ferritin are also induced by inflammatory cytokines such as interleukin (IL)-6, complicating the use of those markers as reflections of iron stores, as will be discussed below. Hepcidin is suppressed by erythroferrone, produced by erythroblasts under conditions of accelerated erythropoiesis such as after blood loss [12], thus facilitating entry of gut iron into the circulation and cycling of iron from macrophages.
Impact of bacterial infections on erythropoiesis
Published in Expert Review of Anti-infective Therapy, 2021
Lara Valente de Souza, Alexander Hoffmann, Günter Weiss
Hepcidin production is regulated mainly by erythropoietic activity, body iron levels, inflammation and hypoxia [13]. During expanded erythropoiesis, it is suppressed by erythroferrone (ERFE), a hormone produced by erythroblasts in the bone marrow (BM) in response to erythropoietin (EPO) [14,15]. Further, hypoxia and/or anemia induced factors such as EPO, hypoxia-inducible factors (HIF) 1 and 2 or platelet-derived growth factor (PDGF)-BB block hepcidin production by different pathways thereby increasing iron delivery for the BM [16–20]. Hepcidin expression is controlled via different signaling pathways including the bone morphogenic protein (BMP)-SMAD signaling cascade along with the Alk2/Alk3 pathway [13,21–23], the inflammation inducible Janus Kinase (JAK)2/STAT3 pathway as well as Erk1/Erk2 or p38 mediated transcriptional control [24,25]. Table 1 summarizes the points of interest approached in this review.
Evaluation of Erythroferrone, Hepcidin, and Iron Overload Status in Iraqi Transfusion-Dependent β-Thalassemia Major Patients
Published in Hemoglobin, 2020
Hasan N.K. Smesam, Hasan A.Q. Albuthabhak, Sareh Arjmand, Hussein K. Al-Hakeim, Seyed Omid R. Siadat
Hepcidin, a small peptide hormone secreted by hepatocyte, and erythroferrone (ERFE) that inhibits the action of hepcidin, is among the central regulators of iron homeostasis in human plasma and promising therapeutic targets for iron disorders. Hepcidin inhibits iron influx into plasma by regulating the cellular concentration of the sole known cellular iron exporter called ferroportin [9,10]. It was found that hepcidin binds to the central cavity of ferroportin in the surface of enterocytes, macrophages and hepatocytes, and blocks its iron export activity. Furthermore, upon hepcidin-binding, conformational changes take place in ferroportin that associate with the exposure of its ubiquitination sites and, therefore, initiation of internalization and degradation [11]. Malfunction of the hepcidin-ferroportin axis underlies some common iron disorders, such as iron overload in β-TM, anemia of inflammation or cancer [12].
Iron Metabolism and Oxidative Status in Patients with Hb H Disease
Published in Hemoglobin, 2019
Xi Yao, Lu-Hong Xu, Hong-Gui Xu, Xin-Yu Li, Yong Liu, Jian-Pei Fang
In humans, hepcidin expression is controlled by iron, inflammation and erythroid regulators. Under high iron conditions, hepcidin expression is increased via the bone morphogenetic protein (BMP) signaling pathway. Inflammation induces the expression of interleukin 6 (IL-6) and activin B in the liver that activates the transcription of hepcidin through the STAT3/JAK2 and the BMP signaling pathways, respectively [13]. Erythroid regulators have not yet been fully elucidated, but erythroferrone (ERFE), which is produced by erythroblasts in response to erythropoietin, plays an important role in suppressing hepcidin expression [14]. In thalassemia, the easily damaged, unstable Hb caused by impaired α-globin chain production and excess β-globin chains leads to ineffective erythropoiesis. Two opposing hepcidin regulatory signals coexist: anemia associated with ineffective erythropoiesis that is an inhibitory signal, and iron loading that is a stimulatory signal [13]. However, the former has a dominant effect on hepcidin expression. Therefore, hepcidin decreases in Hb H disease. As discussed above, low hepcidin levels lead to increased serum ferritin levels.