Limited iron export by hepatocytes contributes to hepatic iron-loading in the Hfe knockout mouse

Chua, Anita; Drake, Sarah F.; Herbison, Carly E.; Olynyk, John K.; Leedman, Peter J.; Trinder, Debbie

doi:10.1016/j.jhep.2005.08.012

Cited by 14 publications

(11 citation statements)

References 22 publications

(40 reference statements)

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“…These increases in hepcidin concentrations were accompanied by a significant decrease in serum iron at 6 h and 10 h in iron-depleted mice (Figure 4C), and a trend toward decreased serum iron in iron-loaded mice. The latter may not have decreased serum iron as efficiently because iron–loaded hepatocytes, macrophages and enterocytes express more ferroportin (Chua et al, 2006; Delaby et al, 2005; Zoller et al, 2002). …”

Section: Resultsmentioning

confidence: 99%

Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism against the Siderophilic Bacterium Vibrio vulnificus

Arezes

Jung

Gabayan

et al. 2015

Cell Host & Microbe

202

182

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SUMMARY Hereditary hemochromatosis, an iron overload disease caused by a deficiency in the iron-regulatory hormone hepcidin, is associated with lethal infections by siderophilic bacteria. To elucidate the mechanisms of this susceptibility, we infected wild-type and hepcidin-deficient mice with the siderophilic bacterium Vibrio vulnificus, and found that hepcidin deficiency results in increased bacteremia and decreased survival of infected mice, which can be partially ameliorated by dietary iron depletion. Additionally, timely administration of hepcidin agonists to hepcidin-deficient mice induces hypoferremia that decreases bacterial loads and rescues these mice from death, regardless of initial iron levels. Studies of Vibrio vulnificus growth ex vivo show that high iron sera from hepcidin-deficient mice support extraordinarily rapid bacterial growth, and that this is inhibited in hypoferremic sera. Our findings demonstrate that hepcidin-mediated hypoferremia is a host defense mechanism against siderophilic pathogens and suggest that hepcidin agonists may improve infection outcomes in patients with hereditary hemochromatosis or thalassemia.

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Section: Resultsmentioning

confidence: 99%

Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism against the Siderophilic Bacterium Vibrio vulnificus

Arezes

Jung

Gabayan

et al. 2015

Cell Host & Microbe

202

182

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“…Molecular studies have shown that control of iron homeostasis is centered mainly on hepcidin-ferroportin-1 interaction (50). It is suggested that ferroportin-1 mediates iron export in hepatocytes (51). Thereby, ferroportin-1 is regulated through systemic regulators that likely include hepcidin (52).…”

Section: Discussionmentioning

confidence: 99%

x-Irradiation in Rat Liver: Consequent Upregulation of Hepcidin and Downregulation of Hemojuvelin and Ferroportin-1 Gene Expression

Christiansen¹,

Sheikh²,

Saile³

et al. 2007

Radiology

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“…Another group of wild-type mice were fed an iron-supplemented diet [2% carbonyl iron (Sigma, St Louis, MO)] for 3 weeks to iron load hepatocytes in vivo. 22 Primary Hepatocyte Culture. Mouse hepatocytes were isolated and cultured from livers of 11-week-old female Hfe knockout and non-iron-loaded wild-type mice as described previously.…”

Section: Animalsmentioning

confidence: 99%

“…Previously, we have shown that ferritin protein levels in Hfe knockout and iron-loaded wild-type hepatocytes were similar, indicating that hepatic iron concentrations were similar, and increased 6-fold compared with non-iron-loaded wild-type hepatocytes. 22 In this study, the hepatocytes were incubated with either 50 nM transferrin (Tfr1 pathway) or 5 m transferrin (Tfr1-independent pathway) at 37°C. Iron uptake by hepatocytes was linear over 2 hours (Fig.…”

Section: Effect Of Transferrin Concentration On Ironmentioning

confidence: 99%

The role of Hfe in transferrin-bound iron uptake by hepatocytes

et al. 2008

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HFE-related hereditary hemochromatosis results in hepatic iron overload. Hepatocytes acquire transferrin-bound iron via transferrin receptor (Tfr) 1 and Tfr1-independent pathways (possibly Tfr2-mediated). In this study, the role of Hfe in the regulation of hepatic transferrin-bound iron uptake by these pathways was investigated using Hfe knockout mice. Iron and transferrin uptake by hepatocytes from Hfe knockout, non-iron-loaded and iron-loaded wild-type mice were measured after incubation with 50 nM 125 I-Tf-59 Fe (Tfr1 pathway) and 5 M 125 I-Tf-59 Fe (Tfr1-independent or putative Tfr2 pathway). Tfr1 and Tfr2 messenger RNA (mRNA) and protein expression were measured by real-time polymerase chain reaction and western blotting, respectively. Tfr1-mediated iron and transferrin uptake by Hfe knockout hepatocytes were increased by 40% to 70% compared with iron-loaded wild-type hepatocytes with similar iron levels and Tfr1 expression. Iron and transferrin uptake by the Tfr1-independent pathway was approximately 100-fold greater than by the Tfr1 pathway and was not affected by the absence of Hfe. Diferric transferrin increased hepatocyte Tfr2 protein expression, resulting in a small increase in transferrin but not iron uptake by the Tfr1-independent pathway. Conclusion: Tfr1-mediated iron uptake is regulated by Hfe in hepatocytes. The Tfr1-independent pathway exhibited a much greater capacity for iron uptake than the Tfr1 pathway but it was not regulated by Hfe. A homozygous C282Y mutation in the HFE gene results in hereditary hemochromatosis and is characterized by increased iron absorption and transferrin saturation that leads to hepatic iron overload. The hemochromatosis protein, HFE, is closely associated with transferrin receptor 1 (TFR1) and competes with transferrin for the same binding sites on TFR1. 1 Hepatocytes acquire transferrin-bound iron via TFR1 by a high-affinity endocytic process. 2 A second transferrin receptor has been identified and was named transferrin receptor 2 (TFR2). Like TFR1, it transports transferrin-bound iron by a receptor-mediated endocytic process, 3 although the affinity of this pathway is up to 30-fold lower than that of TFR1. 4 In iron overload, transferrin saturation and diferric transferrin levels are increased, resulting in an up-regulation of TFR2 protein expression, 5,6 suggesting that hepatocyte iron loading may involve TFR2. It has been postulated that TFR2 may mediate the TFR1-independent uptake process described previously in hepatic cells. [7][8][9] In addition to its role in iron transport, TFR2 also has a role in the regulation of cellular iron metabolism because mutations in TFR2 cause hepatic iron overload. 10,11 TFR2 is predominantly expressed in hepatocytes 12 and has recently been shown to interact with HFE. 13 Unlike TFR1, TFR2 is not regulated by intracellular iron levels because there are no iron-responsive elements in the untranslated region of its messenger RNA (mRNA). 12 Hepcidin is synthesized by hepatocytes and is a key regulator of iron homeostasis. 14 It ...

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Limited iron export by hepatocytes contributes to hepatic iron-loading in the Hfe knockout mouse

Cited by 14 publications

References 22 publications

Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism against the Siderophilic Bacterium Vibrio vulnificus

Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism against the Siderophilic Bacterium Vibrio vulnificus

x-Irradiation in Rat Liver: Consequent Upregulation of Hepcidin and Downregulation of Hemojuvelin and Ferroportin-1 Gene Expression

The role of Hfe in transferrin-bound iron uptake by hepatocytes

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