Ultrastructural Evidence for the Presence of Ferritin–Iron in the Biliary System of Patients With Iron Overload

Cleton, Maud I.; Sindram, Jan W.; Rademakers, L. H. P. M.; Zuyderhoudt, F. M. J.; Bruijn, W. C. de; Marx, Joannes J.M.

doi:10.1002/hep.1840060107

Cited by 23 publications

(4 citation statements)

References 10 publications

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“…The expression of TIM-2 in bile duct epithelial cells suggests that it may be involved in the transport of ferritin into or out of bile. Ferritin excretion into bile is believed to involve lysosomal exocytosis, but the mechanisms of excretion are not well defined (47,48). From our studies, it is possible that this process involves TIM-2.…”

Section: Figure 8 H-ferritin Is Internalized By Cells Expressing Timmentioning

confidence: 79%

TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis

Chen

Chung

et al. 2005

The Journal of Experimental Medicine

198

186

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T cell immunoglobulin-domain and mucin-domain (TIM) proteins constitute a receptor family that was identified first on kidney and liver cells; recently it was also shown to be expressed on T cells. TIM-1 and -3 receptors denote different subsets of T cells and have distinct regulatory effects on T cell function. Ferritin is a spherical protein complex that is formed by 24 subunits of H- and L-ferritin. Ferritin stores iron atoms intracellularly, but it also circulates. H-ferritin, but not L-ferritin, shows saturable binding to subsets of human T and B cells, and its expression is increased in response to inflammation. We demonstrate that mouse TIM-2 is expressed on all splenic B cells, with increased levels on germinal center B cells. TIM-2 also is expressed in the liver, especially in bile duct epithelial cells, and in renal tubule cells. We further demonstrate that TIM-2 is a receptor for H-ferritin, but not for L-ferritin, and expression of TIM-2 permits the cellular uptake of H-ferritin into endosomes. This is the first identification of a receptor for ferritin and reveals a new role for TIM-2.

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Section: Figure 8 H-ferritin Is Internalized By Cells Expressing Timmentioning

confidence: 79%

TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis

Chen

Chung

et al. 2005

The Journal of Experimental Medicine

198

186

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“…114 The form in which iron is released into the bile appears to be variable, and both free iron as well as iron bound to ferritin and Tf have been detected. 92,[112][113][114][115][116][117] A variety of investigations have shown that in addition to endogenous hepatic iron, iron derived from plasma Tf, NTBI, or ferritin, as well as ferritin protein, can be taken up by the liver and rapidly transferred to the bile. 92,[115][116][117] The mechanisms of biliary iron excretion remain poorly characterized but there is some evidence from rats to suggest that ironcontaining lysosomes accumulate at the canalicular membrane and that these are the source of the released iron.…”

Section: Iron Exportmentioning

confidence: 99%

Hepatic Iron Metabolism

2005

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The liver performs three main functions in iron homeostasis. It is the major site of iron storage, it regulates iron traffic into and around the body through its production of the peptide hepcidin, and it is the site of synthesis of major proteins of iron metabolism such as transferrin and ceruloplasmin. Most of the iron that enters the liver is derived from plasma transferrin under normal circumstances, and transferrin receptors 1 and 2 play important roles in this process. In pathological situations, non-transferrin-bound iron, ferritin, and hemoglobin/haptoglobin and heme/hemopexin complexes assume greater importance in iron delivery to the organ. Iron is stored in the liver as ferritin and, with heavy iron loading, as hemosiderin. The liver can divest itself of iron through the plasma membrane iron exporter ferroportin 1, a process that also requires ceruloplasmin. Hepcidin can regulate this iron release through its interaction with ferroportin.

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“…Fe-loaded ferritin, comprised largely of Ftl1, was enriched in the bile from Fe-loaded wild-type (and Slc30a10 KO/KO ) mice at levels sufficient to account for all nonheme Fe. While our study did not address the mechanism of Fe export into bile, Fe-loaded ferritin is most likely exported into the bile via lysosomal exocytosis as previously shown ( 16 , 17 , 18 , 19 , 20 , 21 ). Biliary excretion of excess Fe is unlikely to involve nuclear receptor coactivator 4 (NCOA4), as NCOA4 delivers ferritin to lysosomes in Fe deficiency, not excess ( 40 ).…”

Section: Discussionmentioning

confidence: 80%

“…Transferrin and lactoferrin translocate from the blood to the bile ( 13 , 14 , 15 ). Ferritin is present in the bile and originates from lysosomal exocytosis by hepatocytes ( 16 , 17 , 18 , 19 , 20 , 21 ). However, only transferrin is abundant in the bile under physiologic conditions ( 22 ).…”

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confidence: 99%

Biliary excretion of excess iron in mice requires hepatocyte iron import by Slc39a14

Prajapati

Conboy

Hojyo

et al. 2021

Journal of Biological Chemistry

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Iron is essential for erythropoiesis and other biological processes, but is toxic in excess. Dietary absorption of iron is a highly regulated process and is a major determinant of body iron levels. Iron excretion, however, is considered a passive, unregulated process, and the underlying pathways are unknown. Here we investigated the role of metal transporters SLC39A14 and SLC30A10 in biliary iron excretion. While SLC39A14 imports manganese into the liver and other organs under physiological conditions, it imports iron under conditions of iron excess. SLC30A10 exports manganese from hepatocytes into the bile. We hypothesized that biliary excretion of excess iron would be impaired by SLC39A14 and SLC30A10 deficiency. We therefore analyzed biliary iron excretion in Slc39a14 -and Slc30a10 -deficient mice raised on iron-sufficient and -rich diets. Bile was collected surgically from the mice, then analyzed with nonheme iron assays, mass spectrometry, ELISAs, and an electrophoretic assay for iron-loaded ferritin. Our results support a model in which biliary excretion of excess iron requires iron import into hepatocytes by SLC39A14, followed by iron export into the bile predominantly as ferritin, with iron export occurring independently of SLC30A10. To our knowledge, this is the first report of a molecular determinant of mammalian iron excretion and can serve as basis for future investigations into mechanisms of iron excretion and relevance to iron homeostasis.

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Ultrastructural Evidence for the Presence of Ferritin–Iron in the Biliary System of Patients With Iron Overload

Cited by 23 publications

References 10 publications

TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis

TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis

Hepatic Iron Metabolism

Biliary excretion of excess iron in mice requires hepatocyte iron import by Slc39a14

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