Hepcidin Expression Does Not Rescue the Iron-Poor Phenotype of Kupffer Cells in Hfe-Null Mice After Liver Transplantation

Garuti, Cinzia; Tian, Yinghua; Montosi, Giuliana; Sabelli, Manuela; Corradini, Elena; Graf, Rolf; Ventura, Paolo; Vegetti, Alberto; Clavien, Pierre‐Alain; Pietrangelo, Antonello

doi:10.1053/j.gastro.2010.03.043

Cited by 26 publications

(25 citation statements)

References 34 publications

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“…In contrast, FAC induced a similar upregulation of heme oxygenase-1 mRNA levels irrespective of the HFE genotype ( Figure 1B). These data suggest that monocytes of patients with HFE genotypes associated with risk for iron overload had a partial defect of iron retention reminiscent of that observed in classic HHC, 38 but not reduced oxidative stress.…”

Section: Risk-associated Hfe Genotypes Influence Iron Handling But Nmentioning

confidence: 65%

“…48 In addition, we obtained evidence that, 38 monocytes of patients with HFE genotypes predisposing to mild iron overload show reduced ability to accumulate intracellular iron. Iron-induced upregulation of MCP-1 and IL-6 was hampered in monocytes of patients carrying these disease risk HFE genotypes, thus suggesting that the lack of upregulation of proinflammatory mediators may contribute to explain the lack of association between iron overload and accelerated atherosclerosis in HHC patients and explain the contradictory data on the effect of HFE mutations on vascular damage.…”

Section: Discussionmentioning

confidence: 87%

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Serum Hepcidin and Macrophage Iron Correlate With MCP-1 Release and Vascular Damage in Patients With Metabolic Syndrome Alterations

Valenti

Dongiovanni

Motta

et al. 2011

ATVB

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Objective-Increased body iron stores and hepcidin have been hypothesized to promote atherosclerosis by inducing macrophage iron accumulation and release of cytokines, but direct demonstration in human cells is lacking. The aim of this study was to evaluate the effect of iron on cytokine release in monocytes ex vivo and the correlation with vascular damage and to evaluate the relationship among serum levels of hepcidin, cytokines, and vascular damage in patients with metabolic syndrome alterations. Methods and Results-Manipulation of iron status with ferric ammonium citrate and hepcidin-25 induced monocyte chemoattractant protein (MCP)-1 and interleukin-6 in human differentiating monocytes of patients with hyperferritinemia associated with the metabolic syndrome (nϭ11), but not in subjects with hemochromatosis or HFE mutations impairing iron accumulation (nϭ15), and the degree of induction correlated with the presence of carotid plaques, detected by echocolor-Doppler. In monocytes of healthy subjects (nϭ7), iron and hepcidin increased the mRNA levels and release of MCP-1, but not of interleukin-6. In 130 patients with metabolic alterations, MCP-1 levels, as detected by ELISA, were correlated with hepcidin-25 measured by time-of-flight mass spectrometry (Pϭ0.005) and were an independent predictor of the presence of carotid plaques (Pϭ0.05). Conclusion-Hepcidin

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Section: Risk-associated Hfe Genotypes Influence Iron Handling But Nmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 87%

Serum Hepcidin and Macrophage Iron Correlate With MCP-1 Release and Vascular Damage in Patients With Metabolic Syndrome Alterations

Valenti

Dongiovanni

Motta

et al. 2011

ATVB

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Section: Discussionmentioning

confidence: 99%

“…Mice lacking Hfe only in hepatocytes display a hemochromatosis-like phenotype. 18 HFE may also function in other cells involved in iron recycling, such as Kupffer cells, 19 but its roles have not been fully characterized in cell types other than hepatocytes. We showed that Tfr1 sequesters Hfe, preventing it from participating in the induction of hepcidin expression.…”

Section: Introductionmentioning

confidence: 99%

“…53 HFE may also function in a non hepcidin-dependent manner in Kupffer cells of the recycling compartment. 19 In any case, the observation that mice lacking Hjv or Hfe have inappropriately low hepcidin and Id1 mRNA expression relative to non-heme liver iron stores argues that Hjv-and Hfe-dependent signaling are, at a minimum, partially convergent on the BMP signal transduction cascade, if only indirectly.In our studies, phenotypic parameters and hepcidin mRNA expression were measured at a single time point in mature animals. It is possible that overexpression of Hfe can induce minimal BMP-mediated hepcidin expression in the absence of the BMP co-receptor Hjv, and this might be sufficient over the lifetime of the Hfe transgenic animals to account for the observed influence on liver iron loading.…”

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confidence: 99%

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Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Schmidt

Andrews

Fleming

2010

Blood

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Mutations in HFE cause the most common form of hereditary hemochromatosis (HH). We previously showed that liverspecific, transgenic overexpression of murine Hfe stimulates production of the iron regulatory hormone hepcidin. Here, we developed several additional transgenic mouse strains to further interrogate the structural basis of HFE function in the pathophysiology of HH. We hypothesized that the small, cytoplasmic domain of HFE might be necessary for HFE-mediated induction of hepcidin. We demonstrate that, like the full-length protein, overexpression of Hfe proteins lacking the cytoplasmic domain leads to hepcidin induction, iron deficiency and a hypochromic, microcytic anemia. However, high-level expression of a liver-specific Hfe transgene carrying the mouse equivalent of the common HFE C282Y human diseasecausing mutation (murine C294Y ) IntroductionThe common iron overload disease hereditary hemochromatosis (HH) is caused by a chronic increase in dietary iron absorption. A unifying model has emerged to explain the pathogenesis of genetically distinct forms of HH. 1 Aberrant iron homeostasis results from interruption of a regulatory axis involving the hormone hepcidin, predominantly produced by hepatocytes, and the iron exporter ferroportin, present in duodenal enterocytes and macrophages. Hepcidin binds to ferroportin to trigger its internalization and lysosomal degradation. 2 In this way, circulating hepcidin controls both intestinal iron absorption and the release of iron from macrophages into the plasma. There are 3 general classes of genetic defects known to cause HH. First, recessive mutations in the gene encoding hepcidin (HAMP) prevent the production of functional peptide. 3 Second, some dominant mutations in ferroportin (encoded by SLC40A1) render it resistant to hepcidin regulation. 4,5 Third, recessive mutations in the genes encoding HFE, transferrin receptor-2 (TFR2) or hemojuvelin (HFE2 or HJV), alter hepcidin expression by the hepatocyte. [6][7][8] Most hemochromatosis patients are homozygous for a C282Y mutation in HFE (equivalent to C294Y in mouse Hfe), an atypical major histocompatibility complex (MHC) class I-like molecule 9 that heterodimerizes with ␤2-microglobulin 10 and associates with the major transferrin receptor (TFR1). 11,12 HFE is similar to MHC class I proteins in that it contains a signal sequence, 3 sequential immunoglobulin superfamily ␣-domains, and a transmembrane domain followed by a 19 amino acid, cytoplasmic domain. The cytoplasmic domain of human HFE has 2 conserved, potential phosphorylation sites at 335 Ser and 342 Tyr. Although it has been shown that the cytoplasmic domains of Class I MHC proteins are not necessary for transmitting T-cell activation signals, 13 and overexpression of HFE proteins containing either a S335M or Y342C mutation decreased ferritin levels in HEK293 cells, 14 we hypothesized that these 2 phosphorylation sites might be involved in HFE-mediated hepcidin induction in vivo. Cytoplasmic motifs similar to the YVLA ( 342 Tyr) motif in HFE function ...

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Recurrent Disease Following Liver Transplantation

Maddur

Levitsky

2017

Schiff's Diseases of the Liver

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Hepcidin Expression Does Not Rescue the Iron-Poor Phenotype of Kupffer Cells in Hfe-Null Mice After Liver Transplantation

Cited by 26 publications

References 34 publications

Serum Hepcidin and Macrophage Iron Correlate With MCP-1 Release and Vascular Damage in Patients With Metabolic Syndrome Alterations

Serum Hepcidin and Macrophage Iron Correlate With MCP-1 Release and Vascular Damage in Patients With Metabolic Syndrome Alterations

Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Recurrent Disease Following Liver Transplantation

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