Quantification of Hepcidin-related Iron Accumulation in the Rat Liver (original) (raw)
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The AAPS journal, 2015
High levels of hepcidin, the main regulator of systemic iron metabolism, lead to various diseases. Targeting hepcidin and lowering its concentration is a possible form of intervention in order to treat these diseases. High turnover rate of hepcidin is a major drawback of therapies directly targeting this peptide. We developed two monoclonal antibodies ABT-207 and h5F9-AM8 which inhibit hemojuvelin/repulsive guidance molecule C (RGMc) and downregulate hepcidin. We conducted single-application and dose response studies to understand the antibodies' mechanism and subchronic toxicology studies to exclude safety-related concerns. Investigation was carried out at different biological levels through qPCR, Affymetrix, liquid chromatography coupled with mass spectrometry (LC-MS/MS), histopathology, serum iron, unsaturated iron binding capacity (UIBC), and drug concentration measurements. After a single application of these antibodies, hepcidin expression in liver and its serum protein le...
Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice
Hepatology, 2011
In response to iron loading, hepcidin synthesis is homeostatically increased to limit further absorption of dietary iron and its release from stores. Mutations in HFE, transferrin receptor 2 (Tfr2), hemojuvelin (HJV), or bone morphogenetic protein 6 (BMP6) prevent appropriate hepcidin response to iron, allowing increased absorption of dietary iron, and eventually iron overload. To understand the role each of these proteins plays in hepcidin regulation by iron, we analyzed hepcidin messenger RNA (mRNA) responsiveness to short and long-term iron challenge in iron-depleted Hfe, Tfr2, Hjv, and Bmp6 mutant mice. After 1-day (acute) iron challenge, Hfe 2/2 mice showed a smaller hepcidin increase than their wild-type strain-matched controls, Bmp6 2/2 mice showed nearly no increase, and Tfr2 and Hjv mutant mice showed no increase in hepcidin expression, indicating that all four proteins participate in hepcidin regulation by acute iron changes. After a 21-day (chronic) iron challenge, Hfe and Tfr2 mutant mice increased hepcidin expression to nearly wildtype levels, but a blunted increase of hepcidin was seen in Bmp6 2/2 and Hjv 2/2 mice. BMP6, whose expression is also regulated by iron, may mediate hepcidin regulation by iron stores. None of the mutant strains (except Bmp6 2/2 mice) had impaired BMP6 mRNA response to chronic iron loading. Conclusion: TfR2, HJV, BMP6, and, to a lesser extent, HFE are required for the hepcidin response to acute iron loading, but are partially redundant for hepcidin regulation during chronic iron loading and are not involved in the regulation of BMP6 expression. Our findings support a model in which acute increases in holotransferrin concentrations transmitted through HFE, TfR2, and HJV augment BMP receptor sensitivity to BMPs. A distinct regulatory mechanism that senses hepatic iron may modulate hepcidin response to chronic iron loading. (HEPATOLOGY 2011;53:1333-1341 S ystemic iron homeostasis is dependent on the hepatic peptide hormone hepcidin, its receptor/iron channel ferroportin, and the feedback regulation of the two molecules by iron. Hepcidin controls the delivery of dietary and recycled iron to plasma by binding to the iron exporter ferroportin and inducing its endocytosis and degradation. 1 Increases in body iron levels stimulate hepcidin production in the liver, limiting further absorption of iron. The mechanism of hepcidin regulation by iron is not completely understood. Human studies have shown that blood hepcidin concentrations rapidly increase in response to oral iron challenge, are proportional to increases in diferric transferrin (holotransferrin) concentrations, 2,3 and strongly correlate with iron stores as reflected by serum ferritin. 3 In mice, hepcidin messenger RNA (mRNA) increase within 24 hours after the switch from a lowiron diet to a standard diet 4 and in vivo imaging of hepcidin promoter-reporter constructs in mice 5 confirmed high responsiveness of hepcidin promoter Abbreviations: ANOVA, analysis of variance; apo-Tf, apotransferrin; BMP6, bone morphogenetic protein 6; HJV, hemojuvelin; holo-Tf, holotransferrin; MCV, mean corpuscular volume; mRNA, messenger RNA; qRT-PCR, quantitative reverse-transcription polymerase chain reaction; TfR1, transferrin receptor 1; TfR2, transferrin receptor 2; WT, wild-type.
Therapeutic potential of hepcidin − the master regulator of iron metabolism
Pharmacological Research, 2017
Iron is an essential biogenic element for both prokaryotic and eukaryotic cells. In humans iron is present in hundreds of different metalloproteins. The peptide hormone hepcidin serves as a master regulator of iron homeostasis on the level of single cells and whole organism-by altering cell surface expression of cellular iron exporter-protein ferroportin. Altered levels of extracellular hepcidin lead to pathological conditions such as hemochromatosis and iron loading or, on the other side, iron restrictive anemias. Therapeutic modulation of hepcidin is a new and promising approach to treatment of these conditions. In this review, a summary of the current knowledge of hepcidin function, regulation and pathological involvements are provided, followed by a section covering the therapeutic potential of hepcidin and the current strategies how to modulate its levels and biological functions for therapeutic purposes.
The iron regulatory hormone hepcidin responds to both oral and parenteral iron. Here, we hypothesized that the diverse iron trafficking routes may affect the dynamics and kinetics of the hepcidin activation pathway. To address this, C57BL/6 mice were administered an iron-enriched diet or injected i.p. with iron dextran and analyzed over time. After 1 week of dietary loading with carbonyl iron, mice exhibited significant increases in serum iron and transferrin saturation, as well as in hepatic iron, Smad1/5/8 phosphory-lation and bone morphogenetic protein 6 (BMP6), and hep-cidin mRNAs. Nevertheless, hepcidin expression reached a plateau afterward, possibly due to upregulation of inhibitory Smad7, Id1, and matriptase-2 mRNAs, while hepatic and splenic iron continued to accumulate over 9 weeks. One day following parenteral administration of iron dextran, mice manifested elevated serum and hepatic iron levels and Smad1/5/8 phosphorylation, but no increases in transferrin saturation or BMP6 mRNA. Surprisingly, hepcidin failed to appropriately respond to acute overload with iron dextran, and a delayed (after 5–7 days) hepcidin upregulation correlated with increased transferrin saturation, partial relocation of iron from macrophages to hepatocytes, and induction of BMP6 mRNA. Our data suggest that the physiological hepcidin response is saturable and are consistent with the idea that hepcidin senses exclusively iron compartmental-ized within circulating transferrin and/or hepatocytes.
Journal of Clinical Investigation, 2013
Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β-thalassemia. Thus, the regulation of hepcidin is the subject of interest for the amelioration of the detrimental effects of either iron deficiency or overload. Conflict of interest: The authors have declared that no conflict of interest exists.
Effect of hepcidin on intestinal iron absorption in mice
2010
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Hepcidin as a Regulator of Iron Homeostasis: A Review
https://www.ijhsr.org/IJHSR\_Vol.6\_Issue.2\_Feb2016/54.pdf, 2016
Iron is an essential element for all the cells of the organism. The balance of the levels of iron must be regulated so that the metal is not with low or in surplus levels. The aim of this review was to evaluate the action of hepcidin in the iron homeostasis and its clinical application. Bibliographic survey was carried out on PUBMED, LILACS and Scielo databases, in the period from 2000 to 2015, relating to the hepcidin as a biomarker of iron homeostasis. A total of 76 studies published in international and national magazines were selected. The understanding of the hepcidin function, a small peptide hormone, produced by the liver, contributed for a better understanding of the various mechanisms involved in the iron homeostasis, positioning itself as an important regulator and a pathogenic factor in common disorders of iron. The hepcidin disruption in involved in the several pathologic processes related to the iron disorders. The hepcidin deficiency causes the iron overload in the hereditary hemochromatosis and iron loading anemia, while the surplus of hepcidin contributes for the development of anemias due to iron restriction in inflammatory diseases, infections, some types of cancer and chronic kidney disease. For this reason, the hepcidin can become a useful tool for the diagnostic and provide new therapeutic approaches for diseases associated with the iron deregulation. However, more researches are necessary to clarify the mechanisms of hepcidin in the iron regulation and to outline the contribution in the different disorders of the metabolism of iron.
The emerging role of the liver in iron metabolism
The American journal of gastroenterology, 2005
Iron is essential in health and well-being and its dysregulation is a common theme in disease. Recent advances in our understanding of the molecular biology underlying hemochromatosis and anemia has provided insight into the complex mechanisms implicated in iron metabolism. The proximal small bowel is the major site of iron absorption and, it is becoming increasingly clear that the regulation of this process involves the liver and, in particular, the hepatic antimicrobial peptide hepcidin. A number of studies have shown hepcidin to have an inhibitory function at the level of small bowel iron absorption, although its exact site of action remains to be elucidated. Clearly, identifying the target of hepcidin is of importance and is likely to lead to the development of therapeutic agents in the treatment of iron disorders.
Hepcidin: An emerging hormone in iron homeostasis: A review
International Journal of Chemical Studies, 2021
Hepcidin, is a peptide hormone, which is a key regulator of systemic iron homeostasis and its unbalanced production contributes to iron disorders is derived from liver. Hepcidin was discovered by Krause and coworkers in the year 2000. The name 'Hepcidin' was given, from the place of synthesis in liver hepatocytes (hep-) and its antimicrobial activity (-cidin). The gene encoding hepcidin is expressed in various organs like liver, heart, lungs, brain, spinal cord, intestine, stomach, pancreas, adipocytes, skeletal muscles, testis and macrophages. Hepcidin is a 25 amino acid peptide hormone which inhibits entry of iron into the plasma compartment from the three main sources of iron: dietary absorption in the duodenum, the release of recycled iron from macrophages and the release of stored iron from hepatocytes. This blocking of iron flow is achieved by Hepcidin functios by causing degradation of iron receptor, via an iron transporter ferroportin. Hepcidin production is tightly regulated by (1) increased plasma and liver iron as a feedback mechanism to maintain stable body iron levels, (2) decreased by erythroid activity to ensure iron supply for erythropoiesis and (3) increased by inflammation as a host defense mechanism to limit extracellular iron availability to microbes. Hepcidin levels reflect the integration of signals involved in iron regulation and it directly controls iron absorption and bioavailability in circulation. Its measurement is a useful clinical tool for the management of iron disorders in the body. Recent evidence shows that the deficiency of hepcidin may cause iron overloading even in the much milder common form of hemochromatosis, from mutations in the HFE gene. The discovery of hepcidin and its role in iron metabolism could lead to new therapies for hemochromatosis and anemia of inflammation.