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Hepcidin Production (hepcidin + production)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

New insights into the regulation of iron homeostasis

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2006
R. Deicher
Abstract Hepcidin evolves as a potent hepatocyte-derived regulator of the body's iron distribution piloting the flow of iron via, and directly binding, to the cellular iron exporter ferroportin. The hepcidin-ferroportin axis dominates the iron egress from all cellular compartments that are critical to iron homeostasis, namely placental syncytiotrophoblasts, duodenal enterocytes, hepatocytes and macrophages of the reticuloendothelial system. The gene that encodes hepcidin expression (HAMP) is subject to regulation by proinflammatory cytokines, such as IL-6 and IL-1; excessive hepcidin production explains the relative deficiency of iron during inflammatory states, eventually resulting in the anaemia of inflammation. The haemochromatosis genes HFE (the human leukocyte antigen-related gene), TfR2 (the transferrin receptor-2 gene) and HJV (the haemojuvelin gene) potentially facilitate the transcription of HAMP. Disruption of each of the four genes leads to a diminished hepatic release of hepcidin consistent with both a dominant role of hepcidin in hereditary haemochromatosis and an upstream regulatory role of HFE, TfR2 and HJV on HAMP expression. The engineered generation of hepcidin agonists, mimetics or antagonists could largely broaden current therapeutic strategies to redirect the flow of iron. [source]

Effects of Alcohol Consumption on Iron Metabolism in Mice with Hemochromatosis Mutations

ALCOHOLISM, Issue 1 2007
Jonathan M. Flanagan
Background: Alcoholic liver disease is associated with increased hepatic iron accumulation. The liver-derived peptide hepcidin is the central regulator of iron homeostasis and recent animal studies have demonstrated that exposure to alcohol reduces hepcidin expression. This down-regulation of hepcidin in vivo implies that disturbed iron sensing may contribute to the hepatosiderosis seen in alcoholic liver disease. Alcohol intake is also a major factor in expression of the hemochromatosis phenotype in patients homozygous for the C282Y mutation of the HFE gene. Methods: To assess the effect of alcohol in mice with iron overload, alcohol was administered to mice with disrupted Hfe and IL-6 genes and Tfr2 mutant mice and their respective 129x1/SvJ, C57BL/6J, and AKR/J wild-type congenic strains. Iron absorption, serum iron levels, and hepcidin expression levels were then measured in these mice compared with water-treated control mice. Results: Alcohol was shown to have a strain-specific effect in 129x1/SvJ mice, with treated 129x1/SvJ mice showing a significant increase in iron absorption, serum iron levels, and a corresponding decrease in hepcidin expression. C57BL/6J and AKR/J strain mice showed no effect from alcohol treatment. 129x1/SvJ mice heterozygous or homozygous for the Hfe knockout had a diminished response to alcohol. All 3 strains were shown to have high blood alcohol levels. Conclusions: The effect of alcohol on iron homeostasis is dependent on the genetic background in mice. In an alcohol-susceptible strain, mutation of the Hfe gene diminished the response of the measured iron indices to alcohol treatment. This indicates that either maximal suppression of hepcidin levels had already occurred as a result of the Hfe mutation or that Hfe was a component of the pathway utilized by EtOH in suppressing hepcidin production and increasing iron absorption. [source]

Pentoxifylline improves haemoglobin and interleukin-6 levels in chronic kidney disease

NEPHROLOGY, Issue 3 2010
PAOLO FERRARI
ABSTRACT Aim: To assess whether pentoxifylline improves anaemia of chronic kidney disease (CKD) via suppression of interleukin-6 (IL-6) and improved iron mobilization. Background: CKD patients may have elevated IL-6 and tumour necrosis factor alpha levels. These cytokines can increase hepcidin production, which in turn reduces iron release from macrophages resulting in reduced availability of iron for erythropoiesis. In experimental models, pentoxifylline was shown to reduce IL-6 expression. Methods: We studied 14 patients with stages 4,5 CKD (glomerular filtration rate <30mL/min per 1.73 m2) due to non-inflammatory renal diseases. None of the patients had received immunosuppressive or erythropoietin-stimulating agents or parenteral iron. Patients had weekly blood tests for iron studies and cytokines during a control run-in period of 3 weeks and during 4 weeks of pentoxifylline treatment. Results: Ten patients (eGFR 23 ± 6 mL/min) completed the study. At the end of the run-in period average haemoglobin was 111 ± 5 g/L, ferritin 92 ± 26 µg/L, transferrin saturation 15 ± 3% and circulating IL-6 10.6 ± 3.8 pg/mL. Tumour necrosis factor alpha values were below threshold for detection. Treatment with pentoxifylline reduced circulating IL-6 (6.6 ± 1.6 pg/mL, P < 0.01), increased transferrin saturation (20 ± 5%, P < 0.003) and decreased serum ferritin (81 ± 25 µg/L, P = NS). Haemoglobin increased after the second week of pentoxifylline, reaching 123 ± 6 g/L by week 4 (P < 0.001). Conclusions: Pentoxifylline reduces circulating IL-6 and improves haemoglobin in non-inflammatory moderate to severe CKD. These changes are associated with changes in circulating transferrin saturation and ferritin, suggesting improved iron release. It is hypothesized that pentoxifylline improves iron disposition possibly through modulation of hepcidin. [source]

Urinary hepcidin in congenital chronic anemias

PEDIATRIC BLOOD & CANCER, Issue 1 2007
Susan L. Kearney MD
Abstract Background Hepcidin, a regulator for iron homeostasis, is induced by inflammation and iron burden and suppressed by anemia and hypoxia. This study was conducted to determine the hepcidin levels in patients with congenital chronic anemias. Procedure Forty-nine subjects with anemia, varying degrees of erythropoiesis and iron burden were recruited. Eight children with immune thrombocytopenia were included as approximate age-matched controls. Routine hematologic labs and urinary hepcidin (uhepcidin) levels were assessed. For thalassemia major (TM) patients, uhepcidin was obtained pre- and post-transfusion. Results In TM, uhepcidin levels increased significantly after transfusion, demonstrated wide variance, and the median did not significantly differ from controls or thalassemia intermedia (TI). In both thalassemia syndromes, the hepcidin to ferritin ratio, a marker of the appropriateness of hepcidin expression relative to the degree of iron burden, was low compared to controls. In TI and sickle cell anemia (SCA), median uhepcidin was low compared to controls, P,=,0.013 and <0.001, respectively. In thalassemia subjects, uhepcidin levels were positively associated with ferritin. In subjects with SCA, uhepcidin demonstrated a negative correlation with reticulocyte count. Conclusions This study examines hepcidin levels in congenital anemias. In SCA, hepcidin was suppressed and inversely associated with erythropoietic drive. In thalassemic syndromes, hepcidin was suppressed relative to the degree of iron burden. Transfusion led to increased uhepcidin. In thalassemia, the relative influence of known hepcidin modifiers was more difficult to assess. In thalassemic syndromes where iron overload and anemia have opposing effects, the increased erythropoietic drive may positively influence hepcidin production. Pediatr Blood Cancer 2007;48:57,63. © 2005 Wiley-Liss, Inc. [source]