scholarly journals Ablation of Na + /H + exchanger‐3 prevents iron loading in the Hfe mouse model of hereditary hemochromatosis

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Sydney L Stone ◽  
John P Bonamer ◽  
T Alex Ruwe ◽  
Corbin R Azucenas ◽  
Ali Shawki ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hereditary Hemochromatosis ◽  
Iron Loading

scholarly journals The Effect of the Flavonol Rutin on Serum and Liver Iron Content in a Genetic Mouse Model of Iron Overload

2021 ◽  
Author(s):  
Zachary Hawula ◽  
Eriza Secondes ◽  
Daniel Wallace ◽  
Gautam Rishi ◽  
V. Nathan Subramaniam
Keyword(s):  
Mouse Model ◽  
Iron Overload ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Binding Capacity ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Iron Loading ◽  
Genetic Mouse Model ◽  
Transferrin Receptor 2

The flavonol rutin has been shown to possess antioxidant and iron chelating properties in vitro and in vivo. These dual properties are beneficial as therapeutic options to reduce iron accumulation and the generation of reactive oxygen species resultant from excess free iron. The effect of rutin on iron metabolism has been limited to studies performed in wild type mice either injected or fed high iron diets. The effect of rutin on iron overload caused by genetic dysregulation of iron homeostasis has not yet been investigated. In this study we examined the effect of rutin treatment on tissue iron loading in a genetic mouse model of iron overload, which mirrors the iron loading associated with Type 3 hereditary hemochromatosis patients who have a defect in Transferrin Receptor 2. Male Transferrin Receptor 2 knockout mice were administered rutin via oral gavage for 21 continuous days. Following treatment, iron levels in serum, liver, duodenum, and spleen were assessed. In addition, hepatic ferritin protein levels were determined by western blotting, and expression of iron homeostasis genes by quantitative real-time PCR. Rutin treatment resulted in a significant reduction in hepatic ferritin protein expression and serum transferrin saturation. In addition, trends towards decreased iron levels in the liver and serum, and increased serum unsaturated iron binding capacity were observed. This is the first study to explore the utility of rutin as a potential iron chelator and therapeutic in an animal model of genetic iron overload.

scholarly journals HFE gene knockout produces mouse model of hereditary hemochromatosis

1998 ◽  
Vol 95 (5) ◽  
pp. 2492-2497 ◽  
Author(s):  
X. Y. Zhou ◽  
S. Tomatsu ◽  
R. E. Fleming ◽  
S. Parkkila ◽  
A. Waheed ◽  
...  
Keyword(s):  
Mouse Model ◽  
Gene Knockout ◽  
Hereditary Hemochromatosis ◽  
Hfe Gene

scholarly journals Liver iron sensing and body iron homeostasis

Blood ◽  
2019 ◽  
Vol 133 (1) ◽  
pp. 18-29 ◽  
Author(s):  
Chia-Yu Wang ◽  
Jodie L. Babitt
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Inflammatory Diseases ◽  
Genetic Disorders ◽  
Hereditary Hemochromatosis ◽  
Deficiency Anemia ◽  
Iron Loading ◽  
Liver Iron ◽  
Body Iron ◽  
Iron Supply

Abstract The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.

Altered Hepcidin Regulation in Hereditary Hemochromatosis and Dysmetabolic Hyperferritinemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3590-3590
Author(s):  
Elizabeta Nemeth ◽  
Olivier Loreal ◽  
Caroline Le Lan ◽  
Martine Ropert ◽  
Marie-Bérengère Troadec ◽  
...  
Keyword(s):  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Alcoholic Cirrhosis ◽  
Scar Tissue ◽  
Control Group ◽  
Iron Loading ◽  
Hepatic Diseases ◽  
Hfe Mutations ◽  
Parenchymal Cells ◽  
Hepcidin Mrna

Abstract Hepcidin, the key iron-regulatory hormone synthesized by the liver, blocks iron absorption in duodenum and iron recycling from macrophages. Hepcidin dysregulation is implicated in the pathogenesis of several iron disorders. Hepcidin deficiency was observed in most types of hereditary hemochromatosis, including the HFE-related hemochromatosis, where decreased levels of hepcidin mRNA were found in patients with HFE mutations and in mice lacking HFE. However, levels of the bioactive hepcidin peptide in this disease have not been evaluated. We analyzed urinary hepcidin concentrations in a large cohort of patients with hepatic diseases associated with iron dysregulation, including untreated and treated HFE hemochromatosis (HH), dysmetabolic hyperferritinemia (DYSH) and alcoholic cirrhosis (AC). In untreated HH patients (n=33), hepcidin levels were marginally increased in comparison to controls (n=71). However, the hepcidin/ferritin ratio, an index of appropriateness of hepcidin response to iron load, was decreased in untreated HH group compared to controls, suggesting that hepcidin levels were inappropriately low for the degree of iron loading. In treated HH patients (n=41), hepcidin levels were decreased when compared to either controls or untreated HH group, but the hepcidin/ferritin ratio was not statistically different from the control group ratio. Since hemoglobin levels in the iron-depleted HH group remained unchanged, hepcidin decrease is likely not related to hypoxia, but rather demonstrates partial responsiveness to changes in iron stores. In alcoholic cirrhosis (n=43), hepcidin levels were decreased when compared to controls which may be due to decreased hemoglobin levels observed in these patients and to the replacement of hepcidin-producing hepatocytes by scar tissue. Patients with DYSH (n=40) had increased hepcidin levels in comparison to the controls. Although the underlying cause is yet unclear, the increased hepcidin levels in DYSH could be a contributing factor for the characteristic iron accumulation in both macrophages and parenchymal cells, similar to anemia of chronic diseases. Our study suggests that dysregulation of hepcidin is a likely cause of iron metabolism abnormalities in HH and in DYSH.

Asymptomatic hemochromatosis subjects: genotypic and phenotypic profiles

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3707-3711 ◽  
Author(s):  
Ronald L. Sham ◽  
Richard F. Raubertas ◽  
Caroline Braggins ◽  
Joseph Cappuccio ◽  
Margaret Gallagher ◽  
...  
Keyword(s):  
Iron Overload ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Entire Group ◽  
Iron Loading ◽  
Asymptomatic Patients ◽  
Liver Biopsies ◽  
The Relationship ◽  
Genotypic Profile ◽  
Compound Heterozygotes

Screening for hereditary hemochromatosis (HHC) by means of transferrin saturation (TS) levels has been advocated and will identify many patients who are asymptomatic. The purposes of this study were (1) to determine HFE genotypes among asymptomatic HHC patients and correlate this profile with the degree of iron overload and (2) to evaluate the relationship between mobilized iron (mob Fe), age, serum ferritin (SF), and quantitative hepatic iron (QHI) in this population. One hundred twenty-three asymptomatic HHC patients were evaluated; all had quantitative phlebotomy to determine mob Fe and genotyping for C282Y and H63D mutations. Liver biopsies with QHI determinations were performed on 72 of the 123 patients. Of the entire group, 60% were homozygous for C282Y, and 13% were compound heterozygotes (C282Y/H63D). Among asymptomatic patients, the prevalence of homozygous C282Y is lower compared with previous studies that include clinically affected patients. Of those patients with more than 4 g mob Fe, 77% were homozygous C282Y. Asymptomatic patients with lower iron burdens frequently had genotypes other than homozygous C282Y. There was no correlation between age and mob Fe in these patients; however, there was a correlation between mob Fe and both SF (r = 0.68) and QHI (r = 0.75). In conclusion, asymptomatic patients with moderate iron overload had a different genotypic profile than was seen in advanced iron overload. The significance of identifying patients with modest degrees of iron loading, who may not be homozygous for C282Y, must be addressed if routine TS screening is to be implemented.

scholarly journals Glucose metabolism in the Belgrade rat, a model of iron-loading anemia

2013 ◽  
Vol 304 (12) ◽  
pp. G1095-G1102 ◽  
Author(s):  
Xuming Jia ◽  
Jonghan Kim ◽  
Tania Veuthey ◽  
Chih-Hao Lee ◽  
Marianne Wessling-Resnick
Keyword(s):  
Glucose Metabolism ◽  
Iron Overload ◽  
Hereditary Hemochromatosis ◽  
Pancreatic Tissue ◽  
Iron Loading ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Kidney Morphology ◽  
Urinary Glucose ◽  
Glucose Output

The iron-diabetes hypothesis proposes an association between iron overload and glucose metabolism that is supported by a number of epidemiological studies. The prevalence of type 2 diabetes in patients with hereditary hemochromatosis and iron-loading thalassemia supports this hypothesis. The Belgrade rat carries a mutation in the iron transporter divalent metal transporter 1 (DMT1) resulting in iron-loading anemia. In this study, we characterized the glycometabolic status of the Belgrade rat. Belgrade rats displayed normal glycemic control. Insulin signaling and secretion were not impaired, and pancreatic tissue did not incur damage despite high levels of nonheme iron. These findings suggest that loss of DMT1 protects against oxidative damage to the pancreas and helps to maintain insulin sensitivity despite iron overload. Belgrade rats had lower body weight but increased food consumption compared with heterozygous littermates. The unexpected energy balance was associated with increased urinary glucose output. Increased urinary excretion of electrolytes, including iron, was also observed. Histopathological evidence suggests that altered renal function is secondary to changes in kidney morphology, including glomerulosclerosis. Thus, loss of DMT1 appears to protect the pancreas from injury but damages the integrity of kidney structure and function.

scholarly journals The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4174-4180 ◽  
Author(s):  
Irene E. Zohn ◽  
Ivana De Domenico ◽  
Andrew Pollock ◽  
Diane McVey Ward ◽  
Jessica F. Goodman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cell Surface ◽  
Kupffer Cells ◽  
Transferrin Saturation ◽  
High Serum ◽  
Dominant Negative ◽  
Iron Loading ◽  
Missense Mutations ◽  
Wild Type ◽  
Export Activity

Abstract Ferroportin disease is caused by mutation of one allele of the iron exporter ferroportin (Fpn/IREG1/Slc40a1/MTP1). All reported human mutations are missense mutations and heterozygous null mutations in mouse Fpn do not recapitulate the human disease. Here we describe the flatiron (ffe) mouse with a missense mutation (H32R) in Fpn that affects its localization and iron export activity. Similar to human patients with classic ferroportin disease, heterozygous ffe/+ mice present with iron loading of Kupffer cells, high serum ferritin, and low transferrin saturation. In macrophages isolated from ffe/+ heterozygous mice and through the use of Fpn plasmids with the ffe mutation, we show that Fpnffe acts as a dominant negative, preventing wild-type Fpn from localizing on the cell surface and transporting iron. These results demonstrate that mutations in Fpn resulting in protein mislocalization act in a dominant-negative fashion to cause disease, and the Fpnffe mouse represents the first mouse model of ferroportin disease.

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