The regulation of the hepcidin by modulators of the bone morphogenetic protein (BMP) pathway
type: CreativeWork
description: Hepcidin, the iron regulatory peptide, has emerged as the master regulator of systemic iron homeostasis. Under normal circumstances, hepcidin expression is upregulated by excess iron and inflammation; and downregulated by iron deficiency, anaemia and hypoxia. Insights gained into the pathogenesis of iron-storage disorders such as hereditary haemochromatosis (HH) and hypotransferrinaemia (HPX), have contributed to the identification of the molecular mechanisms governing hepcidin expression. In these disorders, hepcidin expression is inappropriately low, causing increased absorption of iron by the gut thus leading to iron overload. The precise mechanism by which hepcidin is suppressed in these disorders is unclear. The regulation of hepcidin is principally transcriptional, where the Bone Morphogenetic Protein (BMP) pathway has been shown to be a major network governing hepcidin expression. The current study utilised the HPX mouse model to identify potential regulators of hepcidin that are produced locally in liver with a focus on the regulation of hepcidin by the BMP signalling pathway. A known regulator of the BMP pathway, bone morphogenetic protein [BMP]-binding endothelial cell precursor-derived regulator (BMPER), was found to be overexpressed in the HPX mouse liver. Soluble BMPER peptide in excess strongly inhibited BMP-dependent hepcidin promoter activity in both HepG2 and Huh7, cells abolishing the effects of BMP2 and attenuating the effects of BMP6. These effects correlated with reduced cellular pSMAD levels. Addition of recombinant BMPER peptide to primary human hepatocytes strongly downregulated hepcidin mRNA levels and abolished the effects of BMP2. These effects were reflected in vivo where the injection of mice with recombinant BMPER peptide significantly reduced hepcidin mRNA expression which correlated with increased serum iron levels. Thus, the protein may play an important role in suppressing hepcidin production to increase iron availability under cond…
abstract: Hepcidin, the iron regulatory peptide, has emerged as the master regulator of systemic iron homeostasis. Under normal circumstances, hepcidin expression is upregulated by excess iron and inflammation; and downregulated by iron deficiency, anaemia and hypoxia. Insights gained into the pathogenesis of iron-storage disorders such as hereditary haemochromatosis (HH) and hypotransferrinaemia (HPX), have contributed to the identification of the molecular mechanisms governing hepcidin expression. In these disorders, hepcidin expression is inappropriately low, causing increased absorption of iron by the gut thus leading to iron overload. The precise mechanism by which hepcidin is suppressed in these disorders is unclear. The regulation of hepcidin is principally transcriptional, where the Bone Morphogenetic Protein (BMP) pathway has been shown to be a major network governing hepcidin expression. The current study utilised the HPX mouse model to identify potential regulators of hepcidin that are produced locally in liver with a focus on the regulation of hepcidin by the BMP signalling pathway. A known regulator of the BMP pathway, bone morphogenetic protein [BMP]-binding endothelial cell precursor-derived regulator (BMPER), was found to be overexpressed in the HPX mouse liver. Soluble BMPER peptide in excess strongly inhibited BMP-dependent hepcidin promoter activity in both HepG2 and Huh7, cells abolishing the effects of BMP2 and attenuating the effects of BMP6. These effects correlated with reduced cellular pSMAD levels. Addition of recombinant BMPER peptide to primary human hepatocytes strongly downregulated hepcidin mRNA levels and abolished the effects of BMP2. These effects were reflected in vivo where the injection of mice with recombinant BMPER peptide significantly reduced hepcidin mRNA expression which correlated with increased serum iron levels. Thus, the protein may play an important role in suppressing hepcidin production to increase iron availability under cond…
author: Patel, Neeta
language: eng
date published: 2012-10
date modified: 2026-07-24T02:44:42Z
provider: King's College London
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: King's College London