Hepcidin regulation of ferroportin 1 expression in the liver and intestine of the rat

Yeh, Kwo–Yih; Yeh, Mary; Glass, Jonathan

doi:10.1152/ajpgi.00246.2003

Cited by 100 publications

(75 citation statements)

References 44 publications

(61 reference statements)

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“…The iron exporter ferroportin has been shown both to regulate cellular iron uptake by binding to hepcidin (3) and to be transcriptionally downregulated by high hepcidin levels (28). Consistent with the observed lack of hepcidin expression in Hjv-mutant mice, we found high expression of ferroportin in both untreated and sham-injected Hjv-mutant mice ( Figure 4B and data not shown).…”

Section: Generation Of Hjv-mutant Mice and Expression Of Hjv In Peripsupporting

confidence: 87%

“…LPS (1 µg/g body weight; serotype O111: B4; Sigma-Aldrich), IL-6 (12.5 ng/g body weight; R&D Systems), and TNF-α (12.5 ng/g body weight; R&D Systems) were injected intraperitoneally, and organs were isolated for RNA preparation 6 hours after LPS and 4 hours after IL-6 and TNF-α injections (28). Iron-dextran or PBS/dextran/phenolcontrol solution was injected subcutaneously as previously described, and animals were analyzed 7 days after injection (8).…”

Section: Methodsmentioning

confidence: 99%

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Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload

Niederkofler

Salie²,

Arber³

2005

Journal of Clinical Investigation

341

333

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Iron homeostasis plays a critical role in many physiological processes, notably synthesis of heme proteins. Dietary iron sensing and inflammation converge in the control of iron absorption and retention by regulating the expression of hepcidin, a regulator of the iron exporter ferroportin. Human mutations in the glycosylphosphatidylinositol-anchored protein hemojuvelin (HJV; also known as RGMc and HFE2) cause juvenile hemochromatosis, a severe iron overload disease, but the way in which HJV intersects with the iron regulatory network has been unclear. Here we show that, within the liver, mouse Hjv is selectively expressed by periportal hepatocytes and also that Hjv-mutant mice exhibit iron overload as well as a dramatic decrease in hepcidin expression. Our findings define a key role for Hjv in dietary iron sensing and also reveal that cytokine-induced inflammation regulates hepcidin expression through an Hjv-independent pathway.

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Section: Generation Of Hjv-mutant Mice and Expression Of Hjv In Peripsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload

Niederkofler

Salie²,

Arber³

2005

Journal of Clinical Investigation

341

333

View full text Add to dashboard Cite

show abstract

“…Yeh et al have reported that Fpn transcripts are unaltered in the livers of iron-deficient Belgrade rats (in which hepcidin expression is dramatically decreased); these investigators also observed that systemic administration of recombinant hepcidin to rats failed to modify hepatic Fpn mRNA levels. 33 We have found that both Fpn and DMT1 mRNA are increased in the livers of C57Bl6 mice fed a high fat diet or chronically administered 20% ethanol in the drinking water. In neither of these models of fatty liver does the expression of the iron transporters correlate with HAMP mRNA or HIC (O Bergmann and K Brown, in preparation).…”

Section: Iron Regulatory Genes In Cirrhosismentioning

confidence: 82%

Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis?

Bergmann

Mathahs

Broadhurst

et al. 2008

Laboratory Investigation

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Hepatic iron deposition unrelated to hereditary hemochromatosis occurs commonly in cirrhosis but the pathogenesis of this condition is unknown. The aim of this study was to compare the expression of genes involved in the regulation of iron metabolism in cirrhotic (n ¼ 22) and control human livers (n ¼ 5). Transcripts were quantitated by real-time RT-PCR and protein levels were assessed by western blot. Hepatic iron concentrations (HICs) were measured by a spectrophotometric method. Levels of hepcidin mRNA did not differ between controls and cirrhotic livers; there was a highly significant correlation between hepcidin transcript levels and HIC in the latter group. Ferroportin, divalent metal transporter-1 (DMT1), and ferritin heavy chain mRNA levels were significantly higher in cirrhotic human livers than in controls (P ¼ 0.007, 0.039, and 0.025, respectively). By western blot, ferroportin and DMT1 levels were generally diminished in the cirrhotic livers compared to controls; neither correlated with HIC. In contrast, the abundance of ferritin increased with increasing HIC in the cirrhotic livers, whereas transferrin receptor decreased, indicating physiologically appropriate regulation. In conclusion, hepcidin expression appears to be appropriately responsive to iron status in cirrhosis. However, there are complex alterations in DMT1 and ferroportin expression in cirrhotic liver, including decreases in ferroportin and DMT1 at the protein level that may play a role in aberrant regulation of iron metabolism in cirrhosis.

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“…Intraperitoneal injection of bacterial endotoxin (lipopolysaccharide [LPS]) and subcutaneous injection of turpentine were shown to increase hepcidin gene expression in mice. 8,13,14 Inflammation-induced hepcidin gene expression has also been reported in other animal models, including humans, suggesting that hepcidin is a key mediator of anemia of inflammation. 15,16 Cytokines, primarily interleukin 1 (IL-1), tumor necrosis factor ␣, and IL-6, are involved in the regulation of systemic (LPS) and localized (turpentine) inflammation.…”

mentioning

confidence: 86%

Iron- and inflammation-induced hepcidin gene expression in mice is not mediated by Kupffer cellsin vivo

Lou¹,

Lesbordes²,

Nicolas

et al. 2005

Hepatology

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Hepcidin, a recently discovered iron regulatory peptide, is believed to inhibit the release of iron from absorptive enterocytes and macrophages. Liver hepcidin synthesis is induced in vivo by iron stores and inflammation. The molecular basis of the regulation of hepcidin gene expression by these effectors in hepatocytes is currently unknown, although there is strong evidence that indirect mechanisms are involved. The aims of this study were to gain insight into these mechanisms and to determine to what extent other liver cell types are responsible for transducing the signal by which hepcidin expression is regulated in mouse hepatocytes. For this, we depleted Kupffer cells by injection of liposome-encapsulated clodronate and then studied iron-and inflammation-induced hepcidin gene expression. In addition, we directly evaluated the role of the inflammatory cytokine interleukin 6 (IL-6) by using IL-6 -deficient mice. Our results show that iron is able to induce hepcidin gene expression independently of Kupffer cells in the liver and circulating IL-6. In contrast, we show that hepcidin gene induction by inflammation is also independent of Kupffer cells, but involves, at least partly, IL-6. In conclusion, these results show that two independent regulatory pathways control hepcidin gene expression and suggest that hepatocytes play a key role in the regulation of hepcidin gene expression by sensing iron and inflammatory signals. H epcidin is a disulfide-bonded peptide that was first identified as an antimicrobial peptide and was subsequently shown to be a central player in systemic iron homeostasis. Hepcidin is believed to be a negative regulator of dietary iron absorption and iron release by macrophages (for a review, see Ganz 1 ). Complete hepcidin deficiency in mice leads to progressive iron accumulation. This is reminiscent of the phenotype of human hemochromatosis, with predominant iron overload in hepatocytes and iron sparing of the reticuloendothelial cells. 2 Conversely, transgenic animals constitutively expressing the hepcidin gene display iron deficiency anemia. 3 Several mutations in the HAMP gene (human hepcidin) have recently been identified in families with severe juvenile hemochromatosis, confirming the key role of hepcidin in regulating iron homeostasis in humans. [4][5][6][7] The hepcidin gene is expressed predominantly in the liver, where its expression is strictly restricted to hepatocytes. [8][9][10][11] It is synthesized as an 84 -amino acid precursor that is subsequently processed and secreted as a 25-amino acid peptide. This circulating form has been purified from human blood ultrafiltrate and from urine. 9,10 In close correlation with its properties/functions, two main regulators have been shown to control hepcidin gene expression in vivo. First, iron overload, induced experimentally either by iron dextran injection or by iron-rich diet, was found to be associated with an increase in liver hepcidin Abbreviations: IL, interleukin; mRNA, messenger RNA; LPS, lipopolysaccharide; PBS, phosphate-buffe...

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Hepcidin regulation of ferroportin 1 expression in the liver and intestine of the rat

Cited by 100 publications

References 44 publications

Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload

Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload

Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis?

Iron- and inflammation-induced hepcidin gene expression in mice is not mediated by Kupffer cellsin vivo

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