Iron regulation of hepcidin through Hfe and Hjv: Common or distinct pathways?

Pantopoulos, Kostas

doi:10.1002/hep.27777

Cited by 7 publications

(3 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is noteworthy that the hemochromatosis proteins HFE and HJV form a membrane-associated protein complex for hepcidin regulation. This suggests that the two pathways are not fully independent [43,44], and further work should help to better specify the respective roles of the different actors.…”

Section: Normal Iron Metabolismmentioning

confidence: 99%

Iron as a Therapeutic Target in HFE-Related Hemochromatosis: Usual and Novel Aspects

et al. 2018

View full text Add to dashboard Cite

Genetic hemochromatosis is an iron overload disease that is mainly related to the C282Y mutation in the HFE gene. This gene controls the expression of hepcidin, a peptide secreted in plasma by the liver and regulates systemic iron distribution. Homozygous C282Y mutation induces hepcidin deficiency, leading to increased circulating transferrin saturation, and ultimately, iron accumulation in organs such as the liver, pancreas, heart, and bone. Iron in excess may induce or favor the development of complications such as cirrhosis, liver cancer, diabetes, heart failure, hypogonadism, but also complaints such as asthenia and disabling arthritis. Iron depletive treatment mainly consists of venesections that permit the removal of iron contained in red blood cells and the subsequent mobilization of stored iron in order to synthesize hemoglobin for new erythrocytes. It is highly efficient in removing excess iron and preventing most of the complications associated with excess iron in the body. However, this treatment does not target the biological mechanisms involved in the iron metabolism disturbance. New treatments based on the increase of hepcidin levels, by using hepcidin mimetics or inducers, or inhibitors of the iron export activity of ferroportin protein that is the target of hepcidin, if devoid of significant secondary effects, should be useful to better control iron parameters and symptoms, such as arthritis.

show abstract

Section: Normal Iron Metabolismmentioning

confidence: 99%

Iron as a Therapeutic Target in HFE-Related Hemochromatosis: Usual and Novel Aspects

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Inactivation of the HJV (hemojuvelin), a BMP co-receptor, leads to early onset juvenile hemochromatosis, characterized by more severe iron overload. Both HFE and HJV operate as upstream regulators of iron signaling to hepcidin [10].…”

Section: Introductionmentioning

confidence: 99%

Mouse models of hereditary hemochromatosis do not develop early liver fibrosis in response to a high fat diet

et al. 2019

Self Cite

View full text Add to dashboard Cite

Hepatic iron overload, a hallmark of hereditary hemochromatosis, triggers progressive liver disease. There is also increasing evidence for a pathogenic role of iron in non-alcoholic fatty liver disease (NAFLD), which may progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular cancer. Mouse models of hereditary hemochromatosis and NAFLD can be used to explore potential interactions between iron and lipid metabolic pathways. Hfe-/- mice, a model of moderate iron overload, were reported to develop early liver fibrosis in response to a high fat diet. However, this was not the case with Hjv-/- mice, a model of severe iron overload. These data raised the possibility that the Hfe gene may protect against liver injury independently of its iron regulatory function. Herein, we addressed this hypothesis in a comparative study utilizing wild type, Hfe-/-, Hjv-/- and double Hfe-/-Hjv-/- mice. The animals, all in C57BL/6J background, were fed with high fat diets for 14 weeks and developed hepatic steatosis, associated with iron overload. Hfe co-ablation did not sensitize steatotic Hjv-deficient mice to liver injury. Moreover, we did not observe any signs of liver inflammation or fibrosis even in single steatotic Hfe-/- mice. Ultrastructural studies revealed a reduced lipid and glycogen content in Hjv-/- hepatocytes, indicative of a metabolic defect. Interestingly, glycogen levels were restored in double Hfe-/-Hjv-/- mice, which is consistent with a metabolic function of Hfe. We conclude that hepatocellular iron excess does not aggravate diet-induced steatosis to steatohepatitis or early liver fibrosis in mouse models of hereditary hemochromatosis, irrespectively of the presence or lack of Hfe.

show abstract

“…Deletion of the 30-nt IRE leads to the removal of the IRP modulation, and represses IRP independent rate of protein synthesis [11]. In iron deficient cells, binding of the IRP to the IRE (located within the 5'-UTR of target mRNA) blocks mRNA translation by preventing the mRNA-ribosome complex from forming [6,12]. Whereas, in cells with excessive iron levels, iron binds to both IRPs and IREs, and induces conformational changes that promote IRPs dissociation from the target mRNA.…”

Section: Introductionmentioning

confidence: 99%

Iron enhances the binding rates and translational efficiency of iron responsive elements (IREs) mRNA with initiation factor eIF4F

Khan

Domashevskiy

2021

PLoS ONE

View full text Add to dashboard Cite

Interaction of iron responsive elements (IRE) mRNA with the translational machinery is an early step critical in the initiation of protein synthesis. To investigate the binding specificity of IRE mRNA for eIF4F, kinetic rates for the eIF4F·IRE RNA interactions were determined and correlated with the translational efficiency. The observed rate of eIF4F·FRT IRE RNA interactions was 2-fold greater as compared to eIF4F·ACO2 IRE RNA binding. Addition of iron enhanced the association rates and lowered the dissociation rates for the eIF4F binding to both IRE RNAs, with having higher preferential binding to the FRT IRE RNA. The binding rates of both eIF4F·IRE RNA complexes correlated with the enhancement of protein synthesis in vitro. Presence of iron and eIF4F in the depleted WGE significantly enhanced translation for both IRE RNAs. This suggests that iron promotes translation by enhancing the binding rates of the eIF4F∙IRE RNA complex. eIF4F·IRE RNA binding is temperature-dependent; raising the temperature from 5 to 25°C, enhanced the binding rates of eIF4F·FRT IRE (4-fold) and eIF4F·ACO2 IRE (5-fold). Presence of Fe2+ caused reduction in the activation energy for the binding of FRT IRE and ACO2 IRE to eIF4F, suggesting a more stable platform for initiating protein synthesis. In the presence of iron, lowered energy barrier has leads to the faster association rate and slower rate of dissociation for the protein-RNA complex, thus favoring efficient protein synthesis. Our results correlate well with the observed translational efficiency of IRE RNA, thereby suggesting that the presence of iron leads to a rapid, favorable, and stable complex formation that directs regulatory system to respond efficiently to cellular iron levels.

show abstract

Iron regulation of hepcidin through Hfe and Hjv: Common or distinct pathways?

Cited by 7 publications

References 4 publications

Iron as a Therapeutic Target in HFE-Related Hemochromatosis: Usual and Novel Aspects

Iron as a Therapeutic Target in HFE-Related Hemochromatosis: Usual and Novel Aspects

Mouse models of hereditary hemochromatosis do not develop early liver fibrosis in response to a high fat diet

Iron enhances the binding rates and translational efficiency of iron responsive elements (IREs) mRNA with initiation factor eIF4F

Contact Info

Product

Resources

About