Article

Hepcidin suppression and defective iron recycling account for dysregulation of iron homeostasis in heme oxygenase-1 deficiency.

Department of Clinical Chemistry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Journal of Cellular and Molecular Medicine (Impact Factor: 3.7). 10/2008; 13(9B):3091-102. DOI: 10.1111/j.1582-4934.2008.00494.x
Source: PubMed

ABSTRACT Heme oxygenase-1 (HO-1) contribution to iron homeostasis has been postulated, because it facilitates iron recycling by liberating iron mostly from heme catabolism. This enzyme also appears to be responsible for the resolution of inflammatory conditions. In a patient with HO-1 deficiency, inflammation and dysregulation of body iron homeostasis, including anemia and liver and kidney hemosiderosis, are evidenced. Here we postulated that HO-1 is critical in the regulation of ferroportin, the major cellular iron exporter, and hepcidin, the key regulator of iron homeostasis central in the pathogenesis of anemia of inflammation. Our current experiments in human THP-1 monocytic cells indicate a HO-1-induced iron-mediated surface-ferroportin expression, consistent with the role of HO-1 in iron recycling. Surprisingly, we observed low hepcidin levels in the HO-1-deficient patient, despite the presence of inflammation and hemosiderosis, both inducers of hepcidin. Instead, we observed highly increased soluble transferrin receptor levels. This suggests that the decreased hepcidin levels in HO-1 deficiency reflect the increased need for iron in the bone marrow due to the anaemia. Using human hepatoma cells, we demonstrate that HO-activity did not have a direct modulating effect on expression of HAMP, the gene that encodes for hepcidin. Therefore, we argue that the decreased iron recycling may, in part, have contributed to the low hepcidin levels. These findings indicate that dysregulation of iron homeostasis in HO-1 deficiency is the result of both defective iron recycling and erythroid activity-associated inhibition of hepcidin expression. This study therefore shows a crucial role for HO-1 in maintaining body iron balance.

0 Followers
 · 
275 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Heme oxygenease-1 (HO-1) converts heme to biliverdin, carbon monoxide and ferrous ions, but its cellular functions are far beyond heme metabolism. HO-1 via heme removal and degradation products acts as a cytoprotective, anti-inflammatory, immunomodulatory, and pro-angiogenic protein, regulating also a cell cycle. Additionally, HO-1 can translocate to nucleus and regulate transcription factors, so it can also act independently of enzymatic function. Recently, body of evidence has emerged indicating a role for HO-1 in postnatal differentiation of stem and progenitor cells. Maturation of satellite cells, skeletal myoblasts, adipocytes, and osteoclasts is inhibited by HO-1, whereas neurogenic differentiation and formation of cardiomyocytes perhaps can be enhanced. Moreover, HO-1 influences a lineage commitment in pluripotent stem cells and maturation of hematopoietic cells. It may play a role in development of osteoblasts, but descriptions of its exact effects are inconsistent. In this review we discuss a role of HO-1 in cell differentiation, and possible HO-1-dependent signal transduction pathways. Among the potential mediators, we focused on microRNA (miRNA). These small, noncoding RNAs are critical for cell differentiation. Recently we have found that HO-1 not only influences expression of specific miRNAs but also regulates miRNA processing enzymes. It seems that interplay between HO-1 and miRNAs may be important in regulating fates of stem and progenitor cells.
    Antioxidants & Redox Signaling 09/2013; 20(11). DOI:10.1089/ars.2013.5341 · 7.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: AIM: To investigate the effects of the heme oxygenase (HO)-1/carbon monoxide system on iron deposition and portal pressure in rats with hepatic fibrosis induced by bile duct ligation (BDL). METHODS: Male Sprague-Dawley rats were divided randomly into a Sham group, BDL group, Fe group, deferoxamine (DFX) group, zinc protoporphyrin (ZnPP) group and cobalt protoporphyrin (CoPP) group. The levels of HO-1 were detected using different methods. The serum carboxyhemoglobin (COHb), iron, and portal vein pressure (PVP) were also quantified. The plasma and mRNA levels of hepcidin were measured. Hepatic fibrosis and its main pathway were assessed using Van Gieson's stain, hydroxyproline, transforming growth factor-β1 (TGF-β1), nuclear factor-E2-related factor 2 (Nrf2), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1). RESULTS: Serum COHb and protein and mRNA expression levels of HO-1 and Nrf2 were increased in the BDL group compared with the Sham group and were much higher in the CoPP group. The ZnPP group showed lower expression of HO-1 and Nrf2 and lower COHb. The levels of iron and PVP were enhanced in the BDL group but were lower in the ZnPP and DFX groups and were higher in the CoPP and Fe groups. Hepcidin levels were higher, whereas superoxide dismutase levels were increased and malonaldehyde levels were decreased in the ZnPP and DFX groups. The ZnPP group also showed inhibited TGF-β1 expression and regulated TIMP-1/MMP-2 expression, as well as obviously attenuated liver fibrosis. CONCLUSION: Reducing hepatic iron deposition and CO levels by inhibiting HO-1 activity though the Nrf2/Keap pathway could be helpful in improving hepatic fibrosis and regulating PVP.
    World Journal of Gastroenterology 05/2013; 19(19):2921-2934. DOI:10.3748/wjg.v19.i19.2921 · 2.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Heme is essential for the function of all aerobic cells. However, it can be toxic when it occurs in a non-protein bound form; cells maintain a fine balance between heme synthesis and catabolism. The only physiological mechanism of heme degradation is by heme oxygenases (HO). The heme-inducible isoform, HO-1, has been extensively studied in numerous non-erythroid cells, but virtually nothing is known about the expression and potential significance of HO-1 in developing red blood cells (RBC). We have demonstrated that HO-1 is present in erythroid cells and that its expression is upregulated during erythroid differentiation. Overexpression of HO-1 in erythroid cells impairs hemoglobin synthesis, whereas HO-1 absence enhances hemoglobinization in cultured erythroid cells. Based on these results we conclude that HO-1 controls the regulatory heme pool at appropriate levels for any given stage of erythroid differentiation. In summary, our study brings to light the importance of HO-1 expression for erythroid development and expand our knowledge about the fine regulation of hemoglobin synthesis in erythroid cells. Our results indicate that HO-1 plays an important role as a co-regulator of the erythroid differentiation process. Moreover, HO-1 expression must be tightly regulated during red blood cell development.
    Blood 02/2014; 123(14). DOI:10.1182/blood-2013-04-496760 · 9.78 Impact Factor

Full-text (2 Sources)

Download
56 Downloads
Available from
May 16, 2014