Abstract
Little is known about the iron efflux from the pancreas, but it is likely that multicopper ferroxidases (MCFs) are involved in this process. We thus used hephaestin (Heph) and ceruloplasmin (Cp) single-knockout mice and Heph/Cp double-knockout mice to investigate the roles of MCFs in pancreatic iron homeostasis. We found that both HEPH and CP were expressed in the mouse pancreas, and that ablation of either MCF had limited effect on the pancreatic iron levels. However, ablation of both MCFs together led to extensive pancreatic iron deposition and severe oxidative damage. Perls’ Prussian blue staining revealed that this iron deposition was predominantly in the exocrine pancreas, while the islets were spared. Consistent with these results, plasma lipase and trypsin were elevated in Heph/Cp knockout mice, indicating damage to the exocrine pancreas, while insulin secretion was not affected. These data indicate that HEPH and CP play mutually compensatory roles in facilitating iron efflux from the exocrine pancreas, and show that MCFs are able to protect the pancreas against iron-induced oxidative damage.
Highlights
Iron is a redox active metal that can exist in the ferrous or ferric state, and it is essential for many basic physiological processes [1]
We first demonstrated that both CP and HEPH proteins were abundantly expressed in the pancreas of WT mice, and that no CP or HEPH protein was detected in the corresponding gene KO mice as expected (Fig. 1A)
Heph/Cp KO mice displayed the highest levels of ferritin and non-heme iron (900% and 500% of WT respectively), significantly higher than the other models
Summary
Iron is a redox active metal that can exist in the ferrous or ferric state, and it is essential for many basic physiological processes [1]. The safe handling of iron in the body is maintained by a complex interaction among multiple iron-binding proteins, transporters, receptors, ferroxidases, and ferrireductases [3,4]. Disruption of this finely-tuned system can lead to iron overload or iron deficiency and associated adverse effects [2,4]. Three MCFs, namely ceruloplasmin (CP), hephaestin (HEPH), and zyklopen, have been identified in vertebrates [1,5]. Despite their similar function, these MCFs vary widely in tissue distribution. Individuals with mutations in the CP gene (aceruloplasminemia) display significant iron deposition in the liver, glial cells, and, interestingly, in the pancreas [10]
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