Dataset Information

Distinct Iron Deposition Profiles of Liver Zones in Various Models with Iron Homeostasis Disorders.

ABSTRACT: Determination of iron accumulation is crucial in diagnosing the occurrence and progression of many liver- and iron-related diseases. Thus far, little is known about the profiles of iron deposition in different liver zones, particularly under conditions with disordered iron homeostasis. Here, uneven iron distribution in livers of patients with hereditary hemochromatosis (HH) is uncovered, showing the region with the highest iron concentration near the entrance site of the portal vein and hepatic artery in contrast to the sites with the lowest iron concentration close to the distal edge. Distinct iron distribution profiles are also found throughout liver zones in wild-type mice and various mouse models with iron metabolism disorders, including hemochromatosis (Hfe-/- ), iron deficiency, and inflammation. Of note, similar findings observed in HH patients are further demonstrated in Hfe-/- mice. Moreover, the zones with greater iron accumulation appear to be more sensitive to iron changes, e.g., there is iron increase upon iron overload and iron loss in response to iron deficiency. Mechanistic investigation manifests that these differential iron changes in liver zones are subjected to the regulation by the hepcidin-ferroportin axis. Additionally, the data corroborate the reliability of magnetic resonance imaging (MRI) in recognizing the differential iron deposition profiles among liver zones.

SUBMITTER: Song H

PROVIDER: S-EPMC6247051 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Distinct Iron Deposition Profiles of Liver Zones in Various Models with Iron Homeostasis Disorders.

Song Haoyang H Zhang Shuping S Sun Xia X Liu Jing J Wu Yakun Y Guo Wenli W Wang Fudi F Ou Xiaojuan X Cong Min M Jin Erhu E Li Wenyong W Liu Sijin S

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20181012 11

Determination of iron accumulation is crucial in diagnosing the occurrence and progression of many liver- and iron-related diseases. Thus far, little is known about the profiles of iron deposition in different liver zones, particularly under conditions with disordered iron homeostasis. Here, uneven iron distribution in livers of patients with hereditary hemochromatosis (HH) is uncovered, showing the region with the highest iron concentration near the entrance site of the portal vein and hepatic ...[more]

PMID: 30479929

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Project description:Neurotoxicity in all prion disorders is believed to result from the accumulation of PrP-scrapie (PrP(Sc)), a beta-sheet rich isoform of a normal cell-surface glycoprotein, the prion protein (PrP(C)). Limited reports suggest imbalance of brain iron homeostasis as a significant associated cause of neurotoxicity in prion-infected cell and mouse models. However, systematic studies on the generality of this phenomenon and the underlying mechanism(s) leading to iron dyshomeostasis in diseased brains are lacking. In this report, we demonstrate that prion disease-affected human, hamster, and mouse brains show increased total and redox-active Fe (II) iron, and a paradoxical increase in major iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) at the end stage of disease. Furthermore, examination of scrapie-inoculated hamster brains at different timepoints following infection shows increased levels of Tf with time, suggesting increasing iron deficiency with disease progression. Sporadic Creutzfeldt-Jakob disease (sCJD)-affected human brains show a similar increase in total iron and a direct correlation between PrP and Tf levels, implicating PrP(Sc) as the underlying cause of iron deficiency. Increased binding of Tf to the cerebellar Purkinje cell neurons of sCJD brains further indicates upregulation of TfR and a phenotype of neuronal iron deficiency in diseased brains despite increased iron levels. The likely cause of this phenotype is sequestration of iron in brain ferritin that becomes detergent-insoluble in PrP(Sc)-infected cell lines and sCJD brain homogenates. These results suggest that sequestration of iron in PrP(Sc)-ferritin complexes induces a state of iron bio-insufficiency in prion disease-affected brains, resulting in increased uptake and a state of iron dyshomeostasis. An additional unexpected observation is the resistance of Tf to digestion by proteinase-K, providing a reliable marker for iron levels in postmortem human brains. These data implicate redox-iron in prion disease-associated neurotoxicity, a novel observation with significant implications for prion disease pathogenesis.

Dataset Information

Distinct Iron Deposition Profiles of Liver Zones in Various Models with Iron Homeostasis Disorders.

Publications

Distinct Iron Deposition Profiles of Liver Zones in Various Models with Iron Homeostasis Disorders.

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