Interacting signals in the control of hepcidin expression
- 500 Downloads
The amount of iron in the plasma is determined by the regulated release of iron from most body cells, but macrophages, intestinal enterocytes and hepatocytes play a particularly important role in this process. This cellular iron efflux is modulated by the liver-derived peptide hepcidin, and this peptide is now regarded as the central regulator of body iron homeostasis. Hepcidin expression is influenced by systemic stimuli such as iron stores, the rate of erythropoiesis, inflammation, hypoxia and oxidative stress. These stimuli control hepcidin levels by acting through hepatocyte cell surface proteins including HFE, transferrin receptor 2, hemojuvelin, TMPRSS6 and the IL-6R. The surface proteins activate various cell signal transduction pathways, including the BMP-SMAD, JAK-STAT and HIF1 pathways, to alter transcription of HAMP, the gene which encodes hepcidin. It is becoming increasingly apparent that various stimuli can signal through multiple pathways to regulate hepcidin expression, and the interplay between positive and negative stimuli is critical in determining the net hepcidin level. The BMP-SMAD pathway appears to be particularly important and disruption of this pathway will abrogate the response of hepcidin to many stimuli.
KeywordsHepcidin Iron homeostasis Hemochromatosis BMP-SMAD pathway Iron deficiency
GJA is supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia.
- Brittenham GM (1994) The red cell cycle. In: Brock JH, Halliday JW, Pippard MJ, Powell LW (eds) Iron metabolism in health and disease. WB Suanders Company Ltd, London, pp 31–62Google Scholar
- Verga Falzacappa MV, Casanovas G, Hentze MW et al (2008) A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells. J Mol Med 86:531–540. doi: 10.1007/s00109-008-0313-7 PubMedCrossRefGoogle Scholar