Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis

Lesbordes-Brion, Jeanne-Claire; Viatte, Lydie; Bennoun, Myriam; Lou, Dan-Qing; Ramey, Guillemette; Houbron, Christophe; Hamard, Ghislaine; Kahn, Axel; Vaulont, Sophie

doi:10.1182/blood-2006-02-003376

Cited by 225 publications

(207 citation statements)

References 23 publications

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“…The lack of significant cardiac dysfunction in our Hamp −/− mice and in other reported mouse models of impaired hepcidin production (29)(30)(31) is in contrast with the clinical characteristics of juvenile hemochromatosis, in which patients develop severe cardiomyopathy (5). This contrast points to possible differences between human and murine cardiomyocytes in iron entry, export, storage, or detoxification pathways.…”

Section: Discussioncontrasting

confidence: 45%

Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function

Lakhal‐Littleton

Wolna

Carr

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

188

181

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Iron is essential to the cell. Both iron deficiency and overload impinge negatively on cardiac health. Thus, effective iron homeostasis is important for cardiac function. Ferroportin (FPN), the only known mammalian iron-exporting protein, plays an essential role in iron homeostasis at the systemic level. It increases systemic iron availability by releasing iron from the cells of the duodenum, spleen, and liver, the sites of iron absorption, recycling, and storage respectively. However, FPN is also found in tissues with no known role in systemic iron handling, such as the heart, where its function remains unknown. To explore this function, we generated mice with a cardiomyocyte-specific deletion of Fpn. We show that these animals have severely impaired cardiac function, with a median survival of 22 wk, despite otherwise unaltered systemic iron status. We then compared their phenotype with that of ubiquitous hepcidin knockouts, a recognized model of the iron-loading disease hemochromatosis. The phenotype of the hepcidin knockouts was far milder, with normal survival up to 12 mo, despite far greater iron loading in the hearts. Histological examination demonstrated that, although cardiac iron accumulates within the cardiomyocytes of Fpn knockouts, it accumulates predominantly in other cell types in the hepcidin knockouts. We conclude, first, that cardiomyocyte FPN is essential for intracellular iron homeostasis and, second, that the site of deposition of iron within the heart determines the severity with which it affects cardiac function. Both findings have significant implications for the assessment and treatment of cardiac complications of iron dysregulation.

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Section: Discussioncontrasting

confidence: 45%

Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function

Lakhal‐Littleton

Wolna

Carr

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

188

181

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“…Inadequate levels of hepcidin lead to excessive dietary iron absorption (80), excessive mobilization of macrophage iron stores (81), saturation of transferrin with iron, and the appearance of NTBI in plasma (82). Iron overload is also seen in ␤-thalassemia, a genetic disorder resulting from defective ␤-globin synthesis.…”

Section: Pathological Tissue Iron Overloadmentioning

confidence: 99%

“…Despite normal systemic iron homeostasis and circulating hepcidin levels (99), the specific deletion of hepcidin in cardiomyocytes causes cardiac iron depletion and premature death, attributed to increased ferroportin expression in cardiomyocytes and excessive cellular iron efflux. Mice with global deletion of hepcidin may be protected from cardiac iron depletion by increased levels of circulating iron, including NTBI (81). The deletion of ferroportin in cardiomyocytes yields the opposite phenotype, cardiac iron accumulation, but also results in premature death (100).…”

Section: Local Regulation Of Cellular Iron By Hepcidinmentioning

confidence: 99%

Iron homeostasis: An anthropocentric perspective

Coffey

Ganz

2017

Journal of Biological Chemistry

163

167

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The regulation of iron metabolism in biological systems centers on providing adequate iron for cellular function while limiting iron toxicity. Because mammals cannot excrete iron, mechanisms have evolved to control iron acquisition, storage, and distribution at both systemic and cellular levels. Hepcidin, the master regulator of iron homeostasis, controls iron flows into plasma through inhibition of the only known mammalian cellular iron exporter ferroportin. Hepcidin is feedback-regulated by iron status and strongly modulated by inflammation and erythropoietic demand. This review highlights recent advances that have changed our understanding of iron metabolism and its regulation.

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“…In the presence of cytosolic HIF␣, hepcidin is down-regulated and prevented from binding to and internalizing FPT (26,27), thereby increasing the levels of the iron exporter. MPTP treatment alone was observed to result in a decrease of ferroportin levels within the SN (Fig.…”

Section: Phd Inhibition By Dhb Prevents Mptp-induced Losses In Sn Levmentioning

confidence: 99%

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Lee

Rajagopalan

Siddiq

et al. 2009

Journal of Biological Chemistry

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Hypoxia-inducible factor (HIF) plays an important role in cell survival by regulating iron, antioxidant defense, and mitochondrial function. Pharmacological inhibitors of the iron-dependent enzyme class prolyl hydroxylases (PHD), which target ␣ subunits of HIF proteins for degradation, have recently been demonstrated to alleviate neurodegeneration associated with stroke and hypoxic-ischemic injuries. Here we report that inhibition of PHD by 3,4-dihydroxybenzoate (DHB) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic cell loss and up-regulates HIF-1␣ within these neurons. Elevations in mRNA and protein levels of HIF-dependent genes heme oxygenase-1 (Ho-1) and manganese superoxide dismutase (Mnsod) following DHB pretreatment alone are also maintained in the presence of MPTP. MPTP-induced reductions in ferroportin and elevations in nigral and striatal iron levels were reverted to levels comparable with that of untreated controls with DHB pretreatment. Reductions in pyruvate dehydrogenase mRNA and activity resulting from MPTP were also found to be attenuated by DHB. In vitro, the HIF pathway was activated in N27 cells grown at 3% oxygen treated with either PHD inhibitors or an iron chelator. Concordant with our in vivo data, the MPP ؉ -elicited increase in total iron as well as decreases in cell viability were attenuated in the presence of DHB. Taken together, these data suggest that protection against MPTP neurotoxicity may be mediated by alterations in iron homeostasis and defense against oxidative stress and mitochondrial dysfunction brought about by cellular HIF-1␣ induction. This study provides novel data extending the possible therapeutic utility of HIF induction to a Parkinson disease model of neurodegeneration, which may prove beneficial not only in this disorder itself but also in other diseases associated with metal-induced oxidative stress.Parkinson disease (PD) 2 is a neurodegenerative disorder primarily associated with loss of dopaminergic (DAergic) neurons of the pars compacta region of the substantia nigra (SNpc). Dopaminergic neurons are particularly prone to oxidative damage due to high levels of inherent reactive oxygen species that are produced during dopamine synthesis or its breakdown by monoamine oxidases or autoxidation to quinones (1-3). Importantly, iron bound to neuromelanin within DAergic neurons can subsequently react with metabolically liberated hydrogen peroxide through the Fenton reaction to produce extremely toxic hydroxyl radicals. If not properly buffered, hydroxyl radicals can stimulate protein oxidation and lipid peroxidation, which is thought to contribute to macromolecular injury and neuronal death. Iron is the most abundant metal in the brain and some degree of accessible reactive iron is necessary for brain viability as it serves as a cofactor in DNA, RNA, and protein synthesis and for heme and non-heme enzymes involved in both mitochondrial respiration and neurotransmitter synthesis (4). Although iron deficiencies early in life ...

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Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis

Cited by 225 publications

References 23 publications

Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function

Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function

Iron homeostasis: An anthropocentric perspective

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

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