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1.
Int J Mol Sci ; 25(17)2024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39273097

RESUMEN

Iron is a vital element involved in a plethora of metabolic activities. Mammalian systemic iron homeostasis is mainly modulated by hepcidin, the synthesis of which is regulated by a number of proteins, including the hemochromatosis-associated proteins Hfe and Transferrin Receptor 2 (TfR2). Macrophages play versatile functions in iron homeostasis by storing iron derived from the catabolism of erythrocytes and supplying iron required for erythropoiesis. The absence of Hfe in macrophages causes a mild iron deficiency in aged mice and leads to an overproduction of the iron exporter Ferroportin 1 (Fpn1). Conversely, TfR2 gene silencing in macrophages does not influence systemic iron metabolism but decreases transcription of the macrophage Fpn1 in adult mice and modulates their immune response. This study investigated cellular and systemic iron metabolism in adult and aged male mice with macrophage-specific Hfe and TfR2 silencing (double knock-out, DKO). Serum iron parameters were significantly modified in aged animals, and significant differences were found in hepatic hepcidin transcription at both ages. Interestingly, splenic iron content was low in adult DKOs and splenic Fpn1 transcription was significantly increased in DKO animals at both ages, while the protein amount does not reflect the transcriptional trend. Additionally, DKO macrophages were isolated from mice bone marrow (BMDMs) and showed significant variations in the transcription of iron genes and protein amounts in targeted mice compared to controls. Specifically, Tranferrin Receptor 1 (TfR1) increased in DKO adult mice BMDMs, while the opposite is observed in the cells of aged DKO mice. Fpn1 transcript was significantly decreased in the BMDMs of adult DKO mice, while the protein was reduced at both ages. Lastly, a significant increase in Erythropoietin production was evidenced in aged DKO mice. Overall, our study reveals that Hfe and TfR2 in macrophages regulate hepatic Hepc production and affect iron homeostasis in the spleen and BMDMs, leading to an iron deficiency in aged animals that impairs their erythropoiesis.


Asunto(s)
Proteína de la Hemocromatosis , Hierro , Macrófagos , Ratones Noqueados , Receptores de Transferrina , Bazo , Animales , Receptores de Transferrina/metabolismo , Receptores de Transferrina/genética , Bazo/metabolismo , Hierro/metabolismo , Macrófagos/metabolismo , Ratones , Masculino , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Médula Ósea/metabolismo , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Hepcidinas/metabolismo , Hepcidinas/genética , Ratones Endogámicos C57BL , Homeostasis , Hígado/metabolismo
2.
Int J Mol Sci ; 24(10)2023 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-37240294

RESUMEN

Mutations in the HFE/Hfe gene cause Hereditary Hemochromatosis (HH), a highly prevalent genetic disorder characterized by elevated iron deposition in multiple tissues. HFE acts in hepatocytes to control hepcidin expression, whereas HFE actions in myeloid cells are required for cell-autonomous and systemic iron regulation in aged mice. To address the role of HFE specifically in liver-resident macrophages, we generated mice with a selective Hfe deficiency in Kupffer cells (HfeClec4fCre). The analysis of the major iron parameters in this novel HfeClec4fCre mouse model led us to the conclusion that HFE actions in Kupffer cells are largely dispensable for cellular, hepatic and systemic iron homeostasis.


Asunto(s)
Hemocromatosis , Macrófagos del Hígado , Ratones , Animales , Macrófagos del Hígado/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Proteínas de la Membrana/metabolismo , Hígado/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Hemocromatosis/genética , Hemocromatosis/metabolismo , Hierro/metabolismo , Ratones Noqueados
3.
Haematologica ; 106(12): 3149-3161, 2021 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-33054105

RESUMEN

Mutations in HFE cause hereditary hemochromatosis type I hallmarked by increased iron absorption, iron accumulation in hepatocytes and iron deficiency in myeloid cells. HFE encodes an MHC-I like molecule, but its function in immune responses to infection remains incompletely understood. Here, we investigated putative roles of Hfe in myeloid cells and hepatocytes, separately, upon infection with Salmonella Typhimurium, an intracellular bacterium with iron-dependent virulence. We found that constitutive and macrophage-specific deletion of Hfe protected infected mice. The propagation of Salmonella in macrophages was reduced due to limited intramacrophage iron availability for bacterial growth and increased expression of the anti-microbial enzyme nitric oxide synthase-2. By contrast, mice with hepatocyte-specific deletion of Hfe succumbed earlier to Salmonella infection because of unrestricted extracellular bacterial replication associated with high iron availability in the serum and impaired expression of essential host defense molecules such as interleukin-6, interferon-γ and nitric oxide synthase-2. Wild-type mice subjected to dietary iron overload phenocopied hepatocyte-specific Hfe deficiency suggesting that increased iron availability in the serum is deleterious in Salmonella infection and underlies impaired host immune responses. Moreover, the macrophage-specific effect is dominant over hepatocyte-specific Hfe-depletion, as Hfe knock-out mice have increased survival despite the higher parenchymal iron load associated with systemic loss of Hfe. We conclude that cell-specific expression of Hfe in hepatocytes and macrophages differentially affects the course of infections with specific pathogens by determining bacterial iron access and the efficacy of anti-microbial immune effector pathways. This may explain the high frequency and evolutionary conservation of human HFE mutations.


Asunto(s)
Hemocromatosis , Infecciones por Salmonella , Animales , Proteína de la Hemocromatosis/genética , Ratones , Ratones Noqueados , Infecciones por Salmonella/genética , Salmonella typhimurium/genética , Serogrupo
4.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33921027

RESUMEN

Cancer incidence and mortality are rapidly growing, with liver cancer being the sixth most diagnosed cancer worldwide and the third leading cause of cancer death in 2020. A number of risk factors have been identified that trigger the progression to hepatocellular carcinoma. In this review, we focus on iron as a potential risk factor for liver carcinogenesis. Molecules involved in the regulation of iron metabolism are often upregulated in cancer cells, in order to provide a supply of this essential trace element for all stages of tumor development, survival, proliferation, and metastasis. Thus, cellular and systemic iron levels must be tightly regulated to prevent or delay liver cancer progression. Disorders associated with dysregulated iron metabolism are characterized with increased susceptibility to hepatocellular carcinoma. This review discusses the association of iron with metabolic disorders such as hereditary hemochromatosis, non-alcoholic fatty liver disease, obesity, and type 2 diabetes, in the background of hepatocellular carcinoma.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Hierro/metabolismo , Neoplasias Hepáticas/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma Hepatocelular/complicaciones , Humanos , Sobrecarga de Hierro/complicaciones , Neoplasias Hepáticas/complicaciones , Factores de Riesgo
5.
J Pathol ; 241(1): 104-114, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27741349

RESUMEN

Iron is both an essential and a potentially toxic element, and its systemic homeostasis is controlled by the iron hormone hepcidin. Hepcidin binds to the cellular iron exporter ferroportin, causes its degradation, and thereby diminishes iron uptake from the intestine and the release of iron from macrophages. Given that hepcidin-resistant ferroportin mutant mice show exocrine pancreas dysfunction, we analysed pancreata of aging hepcidin knockout (KO) mice. Hepcidin and Hfe KO mice were compared with wild-type (WT) mice kept on standard or iron-rich diets. Twelve-month-old hepcidin KO mice were subjected to daily minihepcidin PR73 treatment for 1 week. Six-month-old hepcidin KO mice showed cytoplasmic acinar iron overload and mild pancreatitis, together with elevated expression of the iron uptake mediators DMT1 and Zip14. Acinar atrophy, massive macrophage infiltration, fatty changes and pancreas fibrosis were noted in 1-year-old hepcidin KO mice. As an underlying mechanism, 6-month-old hepcidin KO mice showed increased pancreatic oxidative stress, with elevated DNA damage, apoptosis and activated nuclear factor-κB (NF-κB) signalling. Neither iron overload nor pancreatic damage was observed in WT mice fed iron-rich diet or in Hfe KO mice. Minihepcidin application to hepcidin KO mice led to an improvement in general health status and to iron redistribution from acinar cells to macrophages. It also resulted in decreased NF-κB activation and reduced DNA damage. In conclusion, loss of hepcidin signalling in mice leads to iron overload-induced chronic pancreatitis that is not seen in situations with less severe iron accumulation. The observed tissue injury can be reversed by hepcidin supplementation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Células Acinares/metabolismo , Hepcidinas/deficiencia , Sobrecarga de Hierro/complicaciones , Pancreatitis Crónica/etiología , Animales , Apoptosis/fisiología , Citoplasma/metabolismo , Modelos Animales de Enfermedad , Hepcidinas/genética , Hepcidinas/fisiología , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/patología , Macrófagos/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica de Transmisión , Estrés Oxidativo/fisiología , Páncreas/ultraestructura , Pancreatitis Crónica/metabolismo , Pancreatitis Crónica/patología
6.
J Biol Chem ; 291(25): 13160-74, 2016 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-27129231

RESUMEN

The hepatic hormone hepcidin is the master regulator of systemic iron homeostasis. Its expression level is adjusted to alterations in iron levels, inflammatory cues, and iron requirements for erythropoiesis. Bone morphogenetic protein 6 (BMP6) contributes to the iron-dependent control of hepcidin. In addition, TGF-ß1 may stimulate hepcidin mRNA expression in murine hepatocytes and human leukocytes. However, receptors and downstream signaling proteins involved in TGF-ß1-induced hepcidin expression are still unclear. Here we show that TGF-ß1 treatment of mouse and human hepatocytes, as well as ectopic expression of TGF-ß1 in mice, increases hepcidin mRNA levels. The hepcidin response to TGF-ß1 depends on functional TGF-ß1 type I receptor (ALK5) and TGF-ß1 type II receptor (TßRII) and is mediated by a noncanonical mechanism that involves Smad1/5/8 phosphorylation. Interestingly, increasing availability of canonical Smad2/3 decreases TGF-ß1-induced hepcidin regulation, whereas the BMP6-hepcidin signal was enhanced, indicating a signaling component stoichiometry-dependent cross-talk between the two pathways. Although ALK2/3-dependent hepcidin activation by BMP6 can be modulated by each of the three hemochromatosis-associated proteins: HJV (hemojuvelin), HFE (hemochromatosis protein), and TfR2 (transferrin receptor 2), these proteins do not control the ALK5-mediated hepcidin response to TGF-ß1. TGF-ß1 mRNA levels are increased in mouse models of iron overload, indicating that TGF-ß1 may contribute to hepcidin synthesis under these conditions. In conclusion, these data demonstrate that a complex regulatory network involving TGF-ß1 and BMP6 may control the sensing of systemic and/or hepatic iron levels.


Asunto(s)
Hepatocitos/metabolismo , Hepcidinas/genética , Factor de Crecimiento Transformador beta1/fisiología , Animales , Proteína Morfogenética Ósea 6/metabolismo , Células Cultivadas , Femenino , Expresión Génica , Hepcidinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Cultivo Primario de Células , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Proteínas Smad/metabolismo , Activación Transcripcional
9.
Biochim Biophys Acta ; 1832(1): 76-84, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22960056

RESUMEN

The inhibitory Smad7 acts as a critical suppressor of hepcidin, the major regulator of systemic iron homeostasis. In this study we define the mRNA expression of the two functionally related Smad proteins, Smad6 and Smad7, within pathways known to regulate hepcidin levels. Using mouse models for hereditary hemochromatosis (Hfe-, TfR2-, Hfe/TfR2-, Hjv- and hepcidin1-deficient mice) we show that hepcidin, Smad6 and Smad7 mRNA expression is coordinated in such a way that it correlates with the activity of the Bmp/Smad signaling pathway rather than with liver iron levels. This regulatory circuitry is disconnected by iron treatment of Hfe-/- and Hfe/TfR2 mice that significantly increases hepatic iron levels as well as hepcidin, Smad6 and Smad7 mRNA expression but fails to augment pSmad1/5/8 levels. This suggests that additional pathways contribute to the regulation of hepcidin, Smad6 and Smad7 under these conditions which do not require Hfe.


Asunto(s)
Péptidos Catiónicos Antimicrobianos/genética , Hemocromatosis/genética , Proteína smad6/genética , Proteína smad7/genética , Animales , Péptidos Catiónicos Antimicrobianos/metabolismo , Modelos Animales de Enfermedad , Femenino , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis , Hepcidinas , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Hierro/metabolismo , Masculino , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Transferrina/deficiencia , Receptores de Transferrina/genética , Proteína smad6/metabolismo , Proteína smad7/metabolismo
10.
Sci Rep ; 14(1): 4887, 2024 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-38418857

RESUMEN

Iron is an essential nutrient for all living organisms. Both iron deficiency and excess can be harmful. Bone, a highly metabolic active organ, is particularly sensitive to fluctuations in iron levels. In this study, we investigated the effects of dietary iron overload on bone homeostasis with a specific focus on two frequently utilized mouse strains: 129/Sv and C57BL/6J. Our findings revealed that after 6 weeks on an iron-rich diet, 129/Sv mice exhibited a decrease in trabecular and cortical bone density in both vertebral and femoral bones, which was linked to reduced bone turnover. In contrast, there was no evidence of bone changes associated with iron overload in age-matched C57BL/6J mice. Interestingly, 129/Sv mice exposed to an iron-rich diet during their prenatal development were protected from iron-induced bone loss, suggesting the presence of potential adaptive mechanisms. Overall, our study underscores the critical role of genetic background in modulating the effects of iron overload on bone health. This should be considered when studying effects of iron on bone.


Asunto(s)
Sobrecarga de Hierro , Hierro de la Dieta , Embarazo , Femenino , Ratones , Animales , Ratones Endogámicos C57BL , Huesos , Ratones Endogámicos , Sobrecarga de Hierro/complicaciones , Hierro
11.
Cell Metab ; 7(2): 173-8, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18249176

RESUMEN

Hereditary hemochromatosis (HH) is a prevalent, potentially fatal disorder of iron metabolism hallmarked by intestinal hyperabsorption of iron, hyperferremia, and hepatic iron overload. In both humans and mice, type I HH is associated with mutations in the broadly expressed HFE/Hfe gene. To identify where Hfe acts to prevent HH, we generated mice with tissue-specific Hfe ablations. This work demonstrates that local Hfe expression in hepatocytes serves to maintain physiological iron homeostasis, answering a long-standing question in medicine and explaining earlier clinical observations.


Asunto(s)
Hemocromatosis/etiología , Hepatocitos/metabolismo , Antígenos de Histocompatibilidad Clase I/fisiología , Proteínas de la Membrana/fisiología , Animales , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/genética , Homeostasis , Hierro/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Mutantes , Mutación
12.
Biochim Biophys Acta ; 1822(7): 1147-53, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22465035

RESUMEN

Quantitative analysis of the temperature dependent AC magnetic susceptibility of freeze-dried mouse tissues from an Hfe hereditary haemochromatosis disease model indicates that iron predominantly appears biomineralised, like in the ferritin cores, in the liver, the spleen and duodenum. The distribution of the amount of ferritin-like iron between genders and genotypes coincides with that of elemental iron and nonheme iron. Importantly, the so-called paramagnetic iron, a quantity also determined from the magnetic data and indicative of nonmineralised iron forms, appears only marginally increased when iron overload takes place.


Asunto(s)
Ferritinas/análisis , Hemocromatosis/metabolismo , Hierro/análisis , Animales , Interpretación Estadística de Datos , Duodeno/química , Duodeno/metabolismo , Femenino , Ferritinas/metabolismo , Hemocromatosis/genética , Hemocromatosis/patología , Hemoglobinas/análisis , Humanos , Hierro/metabolismo , Riñón/química , Riñón/metabolismo , Hígado/química , Hígado/metabolismo , Fenómenos Magnéticos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/química , Miocardio/metabolismo , Nanopartículas/química , Especificidad de Órganos , Espectrofotometría Atómica , Bazo/química , Bazo/metabolismo , Temperatura , Distribución Tisular
13.
Haematologica ; 98(3): 444-7, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22983584

RESUMEN

In conditions of increased erythropoiesis, expression of hepcidin, the master regulator of systemic iron homeostasis, is decreased to allow for the release of iron into the blood stream from duodenal enterocytes and macrophages. It has been suggested that hepcidin suppression is controlled by growth differentiation factor 15 (GDF15), a member of the transforming growth factor-ß superfamily of cytokines that is secreted from developing erythroblasts. In this study, we analyzed iron-related parameters in mice deficient for GDF15 under steady-state conditions and in response to increased erythropoietic activity induced by blood loss. We demonstrate that GDF15 suppresses the hepatic mRNA expression of some BMP/TGFß target genes but not of hepcidin, and show that GDF15 is not required to balance iron homeostasis in response to blood loss.


Asunto(s)
Factor 15 de Diferenciación de Crecimiento/metabolismo , Homeostasis , Hierro/metabolismo , Animales , Médula Ósea/metabolismo , Índices de Eritrocitos , Femenino , Factor 15 de Diferenciación de Crecimiento/genética , Hepcidinas/genética , Hepcidinas/metabolismo , Hierro/sangre , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Flebotomía , ARN Mensajero/genética , ARN Mensajero/metabolismo , Bazo/metabolismo
14.
PLoS One ; 18(11): e0293971, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37930992

RESUMEN

Djungarian hamsters are small rodents that show pronounced physiological acclimations in response to changes in photoperiod, and unfavorable environmental conditions such as reduced food availability and low external temperature. These include substantial adjustments, such as severe body weight loss and the use of daily torpor. Torpor is a state of decreased physiological activity in eutherms, usually marked by low metabolic rate and a reduced body temperature. In this study, we investigated the effects of photoperiodic acclimation and food deprivation on systemic iron metabolism in Djungarian hamsters. Our study illustrates the association between liver iron levels and the incidence of torpor expression during the course of the experiment. Moreover, we show that both, acclimation to short photoperiods and long-term food restriction, associated with iron sequestration in the liver. This effect was accompanied with hypoferremia and mild reduction in the expression of principal iron-hormone, hepcidin. In addition to iron, the levels of manganese, selenium, and zinc were increased in the liver of hamsters under food restriction. These findings may be important factors for regulating physiological processes in hamsters, since iron and other trace elements are essential for many metabolic and physiological processes.


Asunto(s)
Hipotermia , Letargo , Cricetinae , Animales , Phodopus/fisiología , Estaciones del Año , Letargo/fisiología , Fotoperiodo , Ayuno
15.
Semin Hematol ; 58(3): 188-200, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34389111

RESUMEN

Well-controlled iron levels are indispensable for health. Iron deficiency is the most common cause of anemia, whereas iron overload, either hereditary or secondary due to disorders of ineffective erythropoiesis, causes widespread organ failure. Bone is particularly sensitive to fluctuations in systemic iron levels as both iron deficiency and overload are associated with low bone mineral density and fragility. Recent studies have shown that not only iron itself, but also iron-regulatory proteins that are mutated in hereditary hemochromatosis can control bone mass. This review will summarize the current knowledge on the effects of iron on bone homeostasis and bone cell activities, and on the role of proteins that regulate iron homeostasis, i.e. hemochromatosis proteins and proteins of the bone morphogenetic protein pathway, on bone remodeling. As disorders of iron homeostasis are closely linked to bone fragility, deeper insights into common regulatory mechanisms may provide new opportunities to concurrently treat disorders affecting iron homeostasis and bone.


Asunto(s)
Hemocromatosis , Deficiencias de Hierro , Sobrecarga de Hierro , Hemocromatosis/complicaciones , Hemocromatosis/genética , Hemocromatosis/terapia , Homeostasis , Humanos , Hierro/metabolismo , Sobrecarga de Hierro/complicaciones
16.
JBMR Plus ; 3(9): e10206, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31667458

RESUMEN

One of the most prevalent genetic iron overload disorders in Caucasians is caused by mutations in the HFE gene. Both HFE patients and Hfe-mouse models develop a progressive accumulation of iron in the parenchymal cells of various tissues, eventually resulting in liver cirrhosis, hepatocellular carcinoma, cardiomyopathies, hypogonadism, and other pathologies. Clinical data and preclinical models have brought considerable attention to the correlation between iron overload and the development of osteoporosis in HFE/Hfe hemochromatosis. Our study critically challenges this concept. We show that systemic iron overload, at the degree present in Hfe -/- mice, does not associate with the microarchitecture impairment of long bones, thus excluding a negative effect of iron overload on bone integrity. We further reveal that Hfe actions in osteoblasts and osteoclasts are dispensable for the maintenance of bone and iron homeostasis in mice under steady-state conditions. We conclude that, despite systemic iron overload, Hfe -/- mice present normal physiological bone homeostasis. © 2019 The Authors. JBMR Plus in published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

17.
Antioxid Redox Signal ; 29(5): 484-499, 2018 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-29212341

RESUMEN

AIMS: Release of large amounts of free heme into circulation, overproduction of reactive oxygen species (ROS), and activation of toll-like receptor-4-dependent responses are considered critical for the ability of heme to promote oxidative stress and to initiate proinflammatory responses, posing a serious threat to the body. A deep understanding of the consequences of heme overload on the regulation of cellular and systemic iron homeostasis is, however, still lacking. RESULTS: The effects of heme on iron metabolism were studied in primary macrophages and in mouse models of acute and chronic hemolysis. We demonstrated that hemolysis was associated with a significant depletion of intracellular iron levels and increased expression of the sole iron exporter protein, ferroportin. The pathophysiological relevance of this mechanism was further demonstrated in sickle cell anemia mice, which, despite chronic hemolysis, maintained high ferroportin expression and increased iron export. We identified a redox active iron species and superoxide as regulators for ferroportin induction by heme. Scavenging the ROS production, by use of a pharmacological antioxidant N-acetylcysteine, prevented ferroportin induction and normalized intracellular iron levels in macrophages and in experimentally induced hemolysis in mice. INNOVATION: Our data propose that scavenging ROS levels may be a novel therapeutic strategy to balance intracellular iron levels and systemic iron influx in conditions associated with heme overload. CONCLUSION: This study identifies that the pro-oxidant, and not the proinflammatory, actions of heme profoundly impact on iron homeostasis by critically regulating the expression of ferroportin and iron export in hemolytic conditions. Antioxid. Redox Signal. 29, 484-499.


Asunto(s)
Proteínas de Transporte de Catión/genética , Hierro/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Antioxidantes/metabolismo , Modelos Animales de Enfermedad , Hemo/metabolismo , Hemólisis , Lipopolisacáridos/inmunología , Macrófagos/metabolismo , Ratones , Estrés Oxidativo , Bazo/metabolismo
18.
PLoS One ; 7(6): e39363, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22745741

RESUMEN

Regulation of iron homeostasis and the inflammatory response are tightly linked to protect the host from infection. Here we investigate how imbalanced systemic iron homeostasis in a murine disease model of hereditary hemochromatosis (Hfe(-/-) mice) affects the inflammatory responses of the lung. We induced acute pulmonary inflammation in Hfe(-/-) and wild-type mice by intratracheal instillation of 20 µg of lipopolysaccharide (LPS) and analyzed local and systemic inflammatory responses and iron-related parameters. We show that in Hfe(-/-) mice neutrophil recruitment to the bronchoalveolar space is attenuated compared to wild-type mice although circulating neutrophil numbers in the bloodstream were elevated to similar levels in Hfe(-/-) and wild-type mice. The underlying molecular mechanisms are likely multifactorial and include elevated systemic iron levels, alveolar macrophage iron deficiency and/or hitherto unexplored functions of Hfe in resident pulmonary cell types. As a consequence, pulmonary cytokine expression is out of balance and neutrophils fail to be recruited efficiently to the bronchoalveolar compartment, a process required to protect the host from infections. In conclusion, our findings suggest a novel role for Hfe and/or imbalanced iron homeostasis in the regulation of the inflammatory response in the lung and hereditary hemochromatosis.


Asunto(s)
Antígenos de Histocompatibilidad Clase I/metabolismo , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/metabolismo , Infiltración Neutrófila/fisiología , Neumonía/metabolismo , Animales , Hemocromatosis/genética , Hemocromatosis/inmunología , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/genética , Lipopolisacáridos/toxicidad , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Infiltración Neutrófila/genética , Neumonía/inducido químicamente , Neumonía/genética
19.
J Clin Invest ; 121(4): 1386-96, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21364282

RESUMEN

Systemic iron homeostasis is mainly controlled by the liver through synthesis of the peptide hormone hepcidin (encoded by Hamp), the key regulator of duodenal iron absorption and macrophage iron release. Here we show that the liver-specific microRNA miR-122 is important for regulating Hamp mRNA expression and tissue iron levels. Efficient and specific depletion of miR-122 by injection of a locked-nucleic-acid-modified (LNA-modified) anti-miR into WT mice caused systemic iron deficiency, characterized by reduced plasma and liver iron levels, mildly impaired hematopoiesis, and increased extramedullary erythropoiesis in the spleen. Moreover, miR-122 inhibition increased the amount of mRNA transcribed by genes that control systemic iron levels, such as hemochromatosis (Hfe), hemojuvelin (Hjv), bone morphogenetic protein receptor type 1A (Bmpr1a), and Hamp. Importantly, miR-122 directly targeted the 3' untranslated region of 2 mRNAs that encode activators of hepcidin expression, Hfe and Hjv. These data help to explain the increased Hamp mRNA levels and subsequent iron deficiency in mice with reduced miR-122 levels and establish a direct mechanistic link between miR-122 and the regulation of systemic iron metabolism.


Asunto(s)
Hierro/metabolismo , Hígado/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Regiones no Traducidas 3' , Animales , Péptidos Catiónicos Antimicrobianos/genética , Péptidos Catiónicos Antimicrobianos/metabolismo , Sitios de Unión/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Hematopoyesis Extramedular/genética , Hematopoyesis Extramedular/fisiología , Proteína de la Hemocromatosis , Hepcidinas , Antígenos de Histocompatibilidad Clase I/genética , Homeostasis , Hierro/sangre , Deficiencias de Hierro , Masculino , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/antagonistas & inhibidores , Oligonucleótidos/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo
20.
BMC Syst Biol ; 4: 112, 2010 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-20704761

RESUMEN

BACKGROUND: Every cell of the mammalian organism needs iron as trace element in numerous oxido-reductive processes as well as for transport and storage of oxygen. The very versatility of ionic iron makes it a toxic entity which can catalyze the production of radicals that damage vital membranous and macromolecular assemblies in the cell. The mammalian organism maintains therefore a complex regulatory network of iron uptake, excretion and intra-body distribution. Intracellular regulation in different cell types is intertwined with a global hormonal signalling structure. Iron deficiency as well as excess of iron are frequent and serious human disorders. They can affect every cell, but also the organism as a whole. RESULTS: Here, we present a kinematic model of the dynamic system of iron pools and fluxes. It is based on ferrokinetic data and chemical measurements in C57BL6 wild-type mice maintained on iron-deficient, iron-adequate, or iron-loaded diet. The tracer iron levels in major tissues and organs (16 compartment) were followed for 28 days. The evaluation resulted in a whole-body model of fractional clearance rates. The analysis permits calculation of absolute flux rates in the steady-state, of iron distribution into different organs, of tracer-accessible pool sizes and of residence times of iron in the different compartments in response to three states of iron-repletion induced by the dietary regime. CONCLUSIONS: This mathematical model presents a comprehensive physiological picture of mice under three different diets with varying iron contents. The quantitative results reflect systemic properties of iron metabolism: dynamic closedness, hierarchy of time scales, switch-over response and dynamics of iron storage in parenchymal organs. Therefore, we could assess which parameters will change under dietary perturbations and study in quantitative terms when those changes take place.


Asunto(s)
Biología Computacional/métodos , Hierro/metabolismo , Modelos Biológicos , Animales , Transporte Biológico , Fenómenos Biomecánicos , Eritropoyesis , Homeostasis , Humanos , Hierro/sangre , Hierro/farmacocinética , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Factores de Tiempo
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