1. Hepcidin in human iron disorders: Therapeutic implications
Antonello Pietrangelo 
Journal of Hepatology 
Volume 54, Issue 1, Pages (January 2011)
DOI: /j.jhep
Copyright © 2010 European Association for the Study of the Liver Terms and Conditions

2. Fig. 1
Signals and pathways controlling hepcidin expression in the liver. Hepcidin responds to stimulatory signals, such as iron and cytokines, or inhibitory signals, mainly linked to the erythroid activity. The iron-sensing process involves the local iron-induced production of bone morphogenic proteins (BMPs), such as BMP6, and the subsequent assembly of a membrane-associated hetero-tetrameric signaling complex, composed of two type I and two type II serine threonine kinase receptors. This activates a common signal transduction cascade involving the phosphorylation of intracellular receptor-activated Smad1, Smad5 and Smad8, which interact with Smad4 in the cytoplasm. The resulting complex then translocates to the nucleus, where it activates transcription of the hepcidin gene (see text for details). Neogenin, a membrane receptor for RGM, has been proposed to stabilize HJV, and participate in HJV shedding. The soluble form of HJV (sHJV), is thought to compete for BMP binding with its membrane-anchored counterpart (either by sequestering free ligands or by displacing HJV from its BMP-R binding site), thereby providing iron-sensitive modulation of hepcidin expression. SMAD7, which is stimulated by iron, seems to attenuate the signal for hepcidin activation. The serine protease/matriptase 2 (transmembrane serine protease 6, TMPRSS6), inhibits hepcidin expression, most likely by cleaving HJV. Normal HFE interacts with TfR1, and probably also with TfR2. Together, these three proteins might constitute a functional sensing unit responsible for conveying the iron signal to hepcidin. A key mediator of hepcidin response to inflammation is interleukin 6 (IL-6) which stimulates hepcidin transcription through STAT3, although a possible contribution of the BMP/SMD pathway has also been evoked. The C-AMP responsive element binding protein H (CREBH), has been recently implicated in the transcriptional activation of hepcidin during ER stress and seems also to partially contribute to hepcidin response to inflammatory stimuli in vivo. Inhibitory signals for hepcidin transcription include hypoxic inducible factor (HIF), erythropoietin (Epo), or circulating factors derived from maturing erythroblasts in the bone marrow, such as growth differentiation factor (GDF15) and twisted gastrulation protein homolog 1 (TWSG1) (see text for details).
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2010 European Association for the Study of the Liver Terms and Conditions

3. Fig. 2
Hepcidin in the pathogenesis of human hereditary and acquired iron disorders. Abnormal hepcidin regulation is responsible for iron disturbances in paradigmatic human disorders characterized by hepcidin deficiency (HFE-hemochromatosis and thalassemia) or hepcidin excess (anemia of chronic disease or anemia of inflammation). The Figure depicts the liver, as the main site of hepcidin production, and the macrophage, a site for hepcidin activity highly expressing ferroportin, the hepcidin-target. HFE-Hemochromatosis: In HFE-HC, functional loss of HFE due to the C282Y mutation, leads to impaired BMP/SMAD signaling and hepcidin attenuated transcriptional activity (see text for details). The effect of inadequate levels of circulating hepcidin leads to unchecked iron-export by ferroportin in the macrophage, responsible for progressive plasma iron load, tissue iron accumulation and disease. Thalassemia: In hereditary anemias associated with inefficient erythropoiesis, such as thalassemia at early pre-transfusion stages, erythroid factors induced by inefficient erythropoiesis (such as GDF15 and TWSG1) inhibits hepcidin transcription, and cause, in analogy with HFE-HC, hepcidin deficiency and unrestricted iron release from macrophages toward the bloodstream. Anemia of inflammation: During inflammatory states or infection, pathogen by-products may lead to cytokine overproduction, particularly from macrophages and resident Kupffer cells in the liver. The latter may release cytokines, such as IL-6, that stimulate hepcidin production by the hepatocytes. Prolonged hyper-hepcidinemia may then lead to iron sequestration in macrophages, hypoferremia and iron-restricted anemia. In spite of low serum iron, tissue iron excess and inflammatory mediators lead to elevation of serum ferritin.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2010 European Association for the Study of the Liver Terms and Conditions