Regulation of Iron Absorption in Hemoglobinopathies

Rechavi, Gideon; Rivella, Stefano

doi:10.2174/156652408786241401

Cited by 27 publications

(29 citation statements)

References 174 publications

(211 reference statements)

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“…Altered expression of hepcidin is responsible for the modifications of iron metabolism that characterize several diseases, including β-thalassemia (8,12). th3/+ mice have relatively low hepatic Hamp1 expression, suggesting that insufficient hepcidin may be responsible for the high iron levels in these mice (8,13,14). Similarly, low HAMP levels have been measured in the urine of patients with β-thalassemia (15), further supporting this hypothesis.…”

mentioning

confidence: 72%

“…Because the main cause of increased iron absorption in β-thalassemia intermedia is the low expression of Hamp1 (13,14), we utilized transgenic mice overexpressing hepcidin to limit iron overload as a complementary approach to dietary iron restriction. Taken together, our data indicate that a moderate increase in the expression of Hamp1 in th3/+ mice led to hepatic iron levels identical to those in normal mice while splenic iron levels were 4 times less than those in untreated β-thalassemic mice ( Figure 3C).…”

Section: Discussionmentioning

confidence: 99%

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Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Gardenghi¹,

Ramos²,

Marongiu³

et al. 2010

J. Clin. Invest.

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Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.

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confidence: 72%

Section: Discussionmentioning

confidence: 99%

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Gardenghi¹,

Ramos²,

Marongiu³

et al. 2010

J. Clin. Invest.

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209

216

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“…Hbb th3/+ mice develop severe anemia as well as progressive iron overload in the absence of blood transfusions, demonstrating that increased iron absorption plays a critical role in the disease pathogenesis. The mechanism of increased iron absorption is unclear and has not been targeted therapeutically in humans (39). One-month-old Hbb th3/+ mice have a significant increase in liver iron compared with wild-type littermate Hbb +/+ mice as determined by iron staining (Fig.…”

Section: Significancementioning

confidence: 99%

Intestinal HIF2α promotes tissue-iron accumulation in disorders of iron overload with anemia

Anderson¹,

Taylor²,

Xue³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Several distinct congenital disorders can lead to tissue-iron overload with anemia. Repeated blood transfusions are one of the major causes of iron overload in several of these disorders, including β-thalassemia major, which is characterized by a defective β-globin gene. In this state, hyperabsorption of iron is also observed and can significantly contribute to iron overload. In β-thalassemia intermedia, which does not require blood transfusion for survival, hyperabsorption of iron is the leading cause of iron overload. The mechanism of increased iron absorption in β-thalassemia is unclear. We definitively demonstrate, using genetic mouse models, that intestinal hypoxia-inducible factor-2α (HIF2α) and divalent metal transporter-1 (DMT1) are activated early in the pathogenesis of β-thalassemia and are essential for excess iron accumulation in mouse models of β-thalassemia. Moreover, thalassemic mice with established iron overload had significant improvement in tissue-iron levels and anemia following disruption of intestinal HIF2α. In addition to repeated blood transfusions and increased iron absorption, chronic hemolysis is the major cause of tissue-iron accumulation in anemic iron-overload disorders caused by hemolytic anemia. Mechanistic studies in a hemolytic anemia mouse model demonstrated that loss of intestinal HIF2α/DMT1 signaling led to decreased tissue-iron accumulation in the liver without worsening the anemia. These data demonstrate that dysregulation of intestinal hypoxia and HIF2α signaling is critical for progressive iron overload in β-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders.

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“…With no known major physiologic pathway for iron excretion, absorption at the intestine has been found to be the primary site for regulating body iron stores [8]. The expression levels of genes that regulate iron absorption and metabolism differ depending on whether the iron burden is derived from increased iron absorption or through blood transfusion.…”

Section: Basic Iron Metabolism In Scdmentioning

confidence: 99%

Iron Metabolism and Iron Chelation in Sickle Cell Disease

Walter¹,

Harmatz²,

Vichinsky³

2009

Acta Haematol

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This review highlights recent advances in iron metabolism that are relevant to sickle cell disease (SCD). SCD is a common hemoglobinopathy that results in chronic inflammation. Improved understanding of how iron metabolism is controlled by proteins such as hepcidin, ferroportin, hypoxia-inducible factor 1, and growth differentiation factor 15 have revealed how they are involved in the organ toxicity of SCD. SCD patients have lower levels of non-transferrin-bound iron (NTBI) relative to other hemoglobinopathies, such as thalassemia. Care for SCD now commonly uses transfusion that results in iron overload and necessitates the need for chelation. New oral chelation therapy using deferasirox (Exjade/ICL670) appears to be safe and may even lower the amount of toxic free NTBI and enhance patient compliance. Finally, we suggest that iron metabolism and trafficking is different in SCD compared to other hemoglobinopathies. The high levels of inflammatory cytokines in SCD may enhance macrophage/reticuloendothelial cell iron and/or renal cell iron retention. This makes the tissues that retain iron different in SCD, and thus the organs that fail in SCD are different from those of other hemoglobinopathies, such as the cardiomyopathy or endocrinopathies of thalassemia.

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Regulation of Iron Absorption in Hemoglobinopathies

Cited by 27 publications

References 174 publications

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Intestinal HIF2α promotes tissue-iron accumulation in disorders of iron overload with anemia

Iron Metabolism and Iron Chelation in Sickle Cell Disease

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