The bone of the liver (The hepcidin story contd)

doi:10.1016/j.gcb.2010.04.003

Gastroentérologie Clinique et Biologique

Volume 34, Issues 6–7, August–September 2010, Pages 351-354

https://doi.org/10.1016/j.gcb.2010.04.003 Get rights and content

Summary

Iron is an essential trace element in mammalian metabolism. Body iron stores require a tight regulation to avoid detrimental effects due to iron excess or to iron deficiency. Iron losses being not adaptable, iron balance is controlled only through intestinal iron absorption which is regulated by the hepatic peptide hepcidin. Hepcidin synthesis is controlled by several genes including the HFE, hemojuvelin and transferrin receptor 2 genes. Mutations in these genes lead to a phenotype of hemochromatosis. Recently, the bone morphogenetic protein 6 was shown to be the key endogenous ligand involved in the cascade regulating hepcidin synthesis.

Section snippets

Regulation of systemic iron by hepatic hepcidin

Since its discovery in 2001 [1], [2], hepcidin has been shown to play a central role in the regulation of systemic iron homeostasis. This small peptide hormone produced by the liver represses iron efflux from cells by interacting with the iron export protein, ferroportin, especially in duodenal enterocytes and iron-recycling macrophages. Hepcidin binding to ferroportin results in the internalization and lysosomal degradation of ferroportin [3], and, then, in the reduction of both intestinal

Hepcidin-related disorders: A new concept

Hepcidin production is up regulated by iron loading and inflammatory cytokines through two different pathways, the SMAD1/5/8 and STAT3 pathways (Fig. 2). It is down regulated by anaemia and hypoxia independently of iron stores (Table 1).

Anaemia and hereditary hemochromatosis (HH) are the extreme conditions of a spectrum ranging from hepcidin overproduction to hepcidin deficiency.

In inflammatory anaemia as well as in genetic iron-refractory iron-deficiency anaemia (IRIDA), increased production

Identification of the pathway

HJV, bone morphogenetic proteins (BMPs), BMP receptors (BMPR) and mother against decapentaplegic homologue (SMAD) are involved in the iron-driven pathway controlling hepcidin production (Fig. 2). HJV is a member of the repulsive guidance molecules (RGMs) and exists as both a soluble form (sHJV) and a glycosylphosphatidylinositol (GPI)–linked membrane protein [8]. Contrary to other RGMs, HJV is not involved in the development of the central nervous system but is highly expressed in liver, heart

Basic issues

The source of BMP6 and the mechanism whereby BMP6 is itself controlled by iron remain unknown. It is unclear whether BMP6 is locally produced by the liver or can come from other sources. The nature of the iron-sensing signal regulating BMP6 remains also to be clarified. In vitro studies indicate that:

•
HFE is able to bind to both transferrin receptors 1 and 2 by competing with transferrin;
•
induction of hepcidin expression by transferrin requires HFE to be bound to TfR2 and unbound to TfR1 [20],

Conflict of interest

The author has not declared any conflict of interest.

References (24)

C. Pigeon et al.
A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload
J Biol Chem
(2001)
Y. Deugnier et al.
Iron and the liver: update 2008
J Hepatol
(2008)
E. Corradini et al.
The RGM/DRAGON family of BMP co-receptors
Cytokine Growth Factor Rev
(2009)
R.H. Wang et al.
A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression
Cell Metab
(2005)
Y. Xia et al.
Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin
Blood
(2008)
L. Kautz et al.
Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver
Blood
(2008)
L. Silvestri et al.
The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin
Cell Metab
(2008)
P.J. Schmidt et al.
The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression
Cell Metab
(2008)
J. Gao et al.
Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression
Cell Metab
(2009)
E. Corradini et al.
Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis
Gastroenterology
(2009)

J. Milet et al.

Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance

Am J Hum Genet

(2007)

G. Nicolas et al.

Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice

Proc Natl Acad Sci U S A

(2001)

Cited by (4)

Iron, zinc, and copper in retinal physiology and disease
2013, Survey of Ophthalmology
Citation Excerpt :
The membrane-bound human hemochromatosis protein (HFE)112–114,217 controls iron uptake by regulating the interaction between transferrin receptor and transferrin. Iron export by ferroportin is modulated by the iron hormone, hepcidin,57,81,102,114 whose expression is, in turn, regulated by hemojuvelin,111,113,288 the co-receptor for bone morphogenetic protein 6.124 Iron uptake by retinal tissue and individual retinal cells is via transferrin receptor and DMT-1.146,328
The essential trace metals iron, zinc, and copper play important roles both in retinal physiology and disease. They are involved in various retinal functions such as phototransduction, the visual cycle, and the process of neurotransmission, being tightly bound to proteins and other molecules to regulate their structure and/or function or as unbound free metal ions. Elevated levels of “free” or loosely bound metal ions can exert toxic effects, and in order to maintain homeostatic levels to protect retinal cells from their toxicity, appropriate mechanisms exist such as metal transporters, chaperones, and the presence of certain storage molecules that tightly bind metals to form nontoxic products. The pathways to maintain homeostatic levels of metals are closely interlinked, with various metabolic pathways directly and/or indirectly affecting their concentrations, compartmentalization, and oxidation/reduction states. Retinal deficiency or excess of these metals can result from systemic depletion and/or overload or from mutations in genes involved in maintaining retinal metal homeostasis, and this is associated with retinal dysfunction and pathology. Iron accumulation in the retina, a characteristic of aging, may be involved in the pathogenesis of retinal diseases such as age-related macular degeneration (AMD). Zinc deficiency is associated with poor dark adaptation. Zinc levels in the human retina and RPE decrease with age in AMD. Copper deficiency is associated with optic neuropathy, but retinal function is maintained. The changes in iron and zinc homeostasis in AMD have led to the speculation that iron chelation and/or zinc supplements may help in its treatment.
The changing role of liver biopsy in diagnosis and management of haemochromatosis
2011, Pathology
Liver biopsy with histological examination of liver tissue was for many years the cornerstone of the diagnosis of haemochromatosis, allowing assessment of the degree of iron overload and examination of liver histology for the acute and chronic effects of iron overload. In the past two decades the role of liver biopsy in haemochromatosis has changed dramatically. Liver biopsy is rarely requested for two main reasons: (1) genetic testing for human haemochromatosis (HFE) mutations has proved to be very reliable in the diagnosis of haemochromatosis in Caucasian populations, and (2) the majority of patients with haemochromatosis are now diagnosed at an early stage well before permanent tissue damage occurs, so the need to assess tissue and organ damage has diminished. Liver biopsy continues to have a very important role in a small number of haemochromatosis patients for whom it has both diagnostic and prognostic implications. Liver biopsy is essential for the accurate assessment of patients with non-HFE haemochromatosis and in patients who have dual pathology. It is also useful where there appears to be a discrepancy between HFE genotypes and iron studies, particularly in HFE heterozygotes. Finally, liver biopsy is currently the ‘gold standard’ for the diagnosis of fibrosis and cirrhosis, although this is changing as noninvasive methods for assessing fibrosis become more reliable and available. Therefore, it is important that pathologists maintain their knowledge and skills in the use of liver biopsy in haemochromatosis and other iron storage disorders.
Iron Biology – An Overview for Laboratorians
2023, Annals of Clinical and Laboratory Science
Variability of the transferrin receptor 2 gene in AMD
2014, Disease Markers

View full text

Article preview

Gastroentérologie Clinique et Biologique

Summary

Section snippets

Regulation of systemic iron by hepatic hepcidin

Hepcidin-related disorders: A new concept

Identification of the pathway

Basic issues

Conflict of interest

References (24)

A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload

J Biol Chem

Iron and the liver: update 2008

J Hepatol

The RGM/DRAGON family of BMP co-receptors

Cytokine Growth Factor Rev

A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression

Cell Metab

Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin

Blood

Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver

Blood

The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin

Cell Metab

The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression

Cell Metab

Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression

Cell Metab

Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis

Gastroenterology

Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance

Am J Hum Genet

Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice

Proc Natl Acad Sci U S A

Cited by (4)

Iron, zinc, and copper in retinal physiology and disease

The changing role of liver biopsy in diagnosis and management of haemochromatosis

Iron Biology – An Overview for Laboratorians

Variability of the transferrin receptor 2 gene in AMD

Mini reviewThe bone of the liver (The hepcidin story contd)Le « squelette du foie » du foie

Summary

Section snippets

Regulation of systemic iron by hepatic hepcidin

Hepcidin-related disorders: A new concept

Identification of the pathway

Basic issues

Conflict of interest

J Biol Chem

J Hepatol

Cytokine Growth Factor Rev

Cell Metab

Blood

Blood

Cell Metab

Cell Metab

Cell Metab

Gastroenterology

Am J Hum Genet

Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice

Proc Natl Acad Sci U S A

Mini review
The bone of the liver (The hepcidin story contd)Le « squelette du foie » du foie