Abstract
Hepcidin is a key hormone that induces the degradation of ferroportin (FPN), a protein that exports iron from reticuloendothelial macrophages and enterocytes. The aim of the present study was to experimentally evaluate if the obesity induced by a high-fat diet (HFD) modifies the expression of FPN in macrophages and enterocytes, thus altering the iron bioavailability. In order to directly examine changes associated with iron metabolism in vivo, C57BL/6J mice were fed either a control or a HFD. Serum leptin levels were evaluated. The hepcidin, divalent metal transporter-1 (DMT1), FPN and ferritin genes were analyzed by real-time polymerase chain reaction. The amount of iron present in both the liver and spleen was determined by flame atomic absorption spectrometry. Ferroportin localization within reticuloendothelial macrophages was observed by immunofluorescence microscopy. Obese animals were found to exhibit increased hepcidin gene expression, while iron accumulated in the spleen and liver. They also exhibited changes in the sublocation of splenic cellular FPN and a reduction in the FPN expression in the liver and the spleen, while no changes were observed in enterocytes. Possible explanations for the increased hepcidin expression observed in HFD animals may include: increased leptin levels, the liver iron accumulation or endoplasmic reticulum (ER) stress. Together, the results indicated that obesity promotes changes in iron bioavailability, since it altered the iron recycling function.
Highlights
The liver is the main organ responsible for endocrine regulation of iron homeostasis and dictates the amount that is stored; whereas, the homeostatic system fine tunes the availability of iron in the plasma, which, in turn, supplies iron to cells and tissues, safeguarding against iron excess
The liver orchestrates the flow of iron, by regulating the synthesis of hepcidin, a hormone that controls the availability of iron through its interaction with ferroportin (FPN) [1]
Considering that obesity is implicated in eliciting endoplasmic reticulum (ER) stress and that inflammatory parameters were not overtly increased (Figure 1D,E), we assessed whether the hepatic tissue was undergoing ER stress by verifying whether differential splicing occurred at the Xbox-binding protein-1 (XBP-1) gene or eIF2-alpha was being activated by phosphorylation
Summary
The liver is the main organ responsible for endocrine regulation of iron homeostasis and dictates the amount that is stored; whereas, the homeostatic system fine tunes the availability of iron in the plasma, which, in turn, supplies iron to cells and tissues, safeguarding against iron excess. The liver responds to erythropoietic demand and channels most of the systemically-available iron toward synthesis of heme. The liver orchestrates the flow of iron, by regulating the synthesis of hepcidin, a hormone that controls the availability of iron through its interaction with ferroportin (FPN) [1]. Ferroportin is a transmembrane protein responsible for exporting iron from cells, such as duodenal enterocytes and macrophages. Hepcidin prevents the transfer of iron from enterocytes to the portal circulation and disrupts the ability of reticuloendothelial macrophages to furnish iron to the bloodstream
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