Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0162316 (iron deficiency anemia)
 3,806 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in HFE, the most common cause of hereditary hemochromatosis, lead to iron overload. The iron overload is characterized by increased iron uptake due to lower levels of the hepatic, iron regulatory hormone hepcidin. HFE was cloned 21 years ago, but the signaling pathway is still unknown. Because bone morphogenetic protein (BMP) signaling is impaired in patients with hereditary hemochromatosis, and the interaction of HFE and the BMP type I receptor ALK3 was suggested in vitro, in vivo experiments were performed. In vivo, hepatocyte-specific Alk3-deficient and control mice were injected with either AAV2/8-Hfe-Flag or PBS. HFE overexpression in control mice results in increased hepatic hepcidin levels, p-Smad1/5 levels, and iron deficiency anemia, whereas overexpression of HFE in hepatocyte-specific Alk3-deficient mice results in no change in hepcidin, p-Smad1/5 levels, or blood parameters. These results indicate that HFE signals predominantly via ALK3 to induce hepcidin in vivo.
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PMID:The hemochromatosis protein HFE signals predominantly via the BMP type I receptor ALK3 in vivo. 3027 47

Hepcidin, the main regulator of iron metabolism, is synthesized and released by hepatocytes in response to increased body iron concentration and inflammation. Deregulation of hepcidin expression is a common feature of genetic and acquired iron disorders: in Hereditary Hemochromatosis (HH) and iron-loading anemias low hepcidin causes iron overload, while in Iron Refractory Iron Deficiency Anemia (IRIDA) and anemia of inflammation (AI), high hepcidin levels induce iron-restricted erythropoiesis. Hepcidin expression in the liver is mainly controlled by the BMP-SMAD pathway, activated in a paracrine manner by BMP2 and BMP6 produced by liver sinusoidal endothelial cells. The BMP type I receptors ALK2 and ALK3 are responsible for iron-dependent hepcidin upregulation and basal hepcidin expression, respectively. Characterization of animal models with genetic inactivation of the key components of the pathway has suggested the existence of two BMP/SMAD pathway branches: the first ALK3 and HH proteins dependent, responsive to BMP2 for basal hepcidin activation, and the second ALK2 dependent, activated by BMP6 in response to increased tissue iron. The erythroid inhibitor of hepcidin Erythroferrone also impacts on the liver BMP-SMAD pathway although its effect is blunted by pathway hyper-activation. The liver BMP-SMAD pathway is required also in inflammation to cooperate with JAK2/STAT3 signaling for full hepcidin activation. Pharmacologic targeting of BMP-SMAD pathway components or regulators may improve the outcome of both genetic and acquired disorders of iron overload and deficiency by increasing or inhibiting hepcidin expression.
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PMID:Hepcidin and the BMP-SMAD pathway: An unexpected liaison. 3079 17