RESUMEN
Hemachromatosis (iron-overload) increases host susceptibility to siderophilic bacterial infections that cause serious complications, but the underlying mechanisms remain elusive. The present study demonstrates that oral infection with hyperyersiniabactin (Ybt) producing Yersinia pseudotuberculosis Δfur mutant (termed Δfur) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δfur-infected intestine revealed up-regulation in cytokine-cytokine receptor interactions, the complement and coagulation cascade, the NF-κB signaling pathway, and chemokine signaling pathways, and down-regulation in cell-adhesion molecules and Toll-like receptor signaling pathways. Further studies indicate that dysregulated interleukin (IL)-1ß signaling triggered in hemachromatotic mice infected with Δfur damages the intestinal barrier by activation of myosin light-chain kinases (MLCK) and excessive neutrophilia. Inhibiting MLCK activity or depleting neutrophil infiltration reduces barrier disruption, largely ameliorates immunopathology, and substantially rescues hemochromatotic mice from lethal Δfur infection. Moreover, early intervention of IL-1ß overproduction can completely rescue hemochromatotic mice from the lethal infection.
Asunto(s)
Hemocromatosis/metabolismo , Intestinos/metabolismo , Infecciones por Yersinia pseudotuberculosis/metabolismo , Yersinia pseudotuberculosis/metabolismo , Animales , Proteínas Bacterianas/genética , Proteínas de Unión al Calcio/metabolismo , Citocinas/metabolismo , Inflamación , Interleucina-1beta/metabolismo , Intestinos/patología , Ratones , Quinasa de Cadena Ligera de Miosina/metabolismo , FN-kappa B/metabolismo , Proteínas Represoras/genética , Sideróforos/metabolismo , Transducción de Señal , Transcriptoma , Yersinia pseudotuberculosis/genéticaRESUMEN
Hemochromatosis (HC) is a genetically heterogeneous disorder in which uncontrolled intestinal iron absorption may lead to progressive iron overload (IO) responsible for disabling and life-threatening complications such as arthritis, diabetes, heart failure, hepatic cirrhosis, and hepatocellular carcinoma. The recent advances in the knowledge of pathophysiology and molecular basis of iron metabolism have highlighted that HC is caused by mutations in at least 5 genes, resulting in insufficient hepcidin production or, rarely, resistance to hepcidin action. This has led to an HC classification based on different molecular subtypes, mainly reflecting successive gene discovery. This scheme was difficult to adopt in clinical practice and therefore needs revision. Here we present recommendations for unambiguous HC classification developed by a working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society), including both clinicians and basic scientists during a meeting in Heidelberg, Germany. We propose to deemphasize the use of the molecular subtype criteria in favor of a classification addressing both clinical issues and molecular complexity. Ferroportin disease (former type 4a) has been excluded because of its distinct phenotype. The novel classification aims to be of practical help whenever a detailed molecular characterization of HC is not readily available.
Asunto(s)
Proteínas de Transporte de Catión , Hemocromatosis , Sobrecarga de Hierro , Proteínas de Transporte de Catión/metabolismo , Hemocromatosis/diagnóstico , Hemocromatosis/genética , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis , Hepcidinas/genética , Hepcidinas/metabolismo , Humanos , Hierro/metabolismoRESUMEN
The liver plays a crucial role in maintaining systemic iron homeostasis through iron storage, sensing of systemic iron needs, and production of the iron-regulatory hormone hepcidin. While mice are commonly used as models for studying human iron homeostasis, their liver structure differs significantly from humans. Since the mouse liver is structured in six separated lobes, often, the analysis of a single defined lobe is preferred due to concerns over data reproducibility between experimental cohorts. In this study, we compared iron-related parameters in distinct liver lobes of C57BL/6 wild-type mice across different ages. We found that the non-heme iron levels, as well as the mRNA and protein expression of iron storage protein Ferritin and the iron importer Transferrin Receptor 1, were similar between liver lobes. Additionally, the mRNA expression of Hepcidin, as well as its regulators, Bmp2 and Bmp6, and iron importers Zip8 and Zip14 were comparable. Minor differences were observed in Ferroportin mRNA levels of 24-wk-old mice; however, this did not correlate with altered iron content. The findings in wild-type mice were reproduced in Hfe knock-out mice - a well-established genetic model of the most prevalent form of hemochromatosis. Overall, our results indicate that C57BL/6 mouse liver lobes can be used interchangeably for assessing iron content and expression of iron-related genes. Understanding if these findings are applicable to other mouse developmental stages, strains, or models of (iron-related) disorders will be key to promote reduction of experimental animal numbers and facilitate resource sharing among research groups studying liver iron homeostasis.NEW & NOTEWORTHY This study reveals that, despite being structurally separated, liver lobes from C57BL/6 wild-type and iron-overloaded mice can be used interchangeably for the evaluation of iron content and expression of iron-related genes.
Asunto(s)
Hemocromatosis , Hepcidinas , Ratones , Humanos , Animales , Hepcidinas/genética , Hepcidinas/metabolismo , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Antígenos de Histocompatibilidad Clase I , Reproducibilidad de los Resultados , Ratones Endogámicos C57BL , Hígado/metabolismo , Hemocromatosis/metabolismo , Hierro/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratones Noqueados , HomeostasisRESUMEN
BACKGROUND: Hereditary hemochromatosis (HH) is characterized by iron overload that can cause multiple organ dysfunction primarily due to uncontrolled iron-mediated oxidative stress. Although HH leads to muscular weakness, disorder, and fatigue, the mechanism by which HH affects skeletal muscle physiology is largely unknown. METHODS: Using Hfe knockout mice (6-7 months old), a well-defined mouse model of HH, we examined iron status in the skeletal muscle, as well as other organs. As mitochondria are key organelle for muscular function, this study also explored how molecular markers for mitochondrial function and related systems are regulated in the HH skeletal muscle using western blots. RESULTS: Although iron overload was evident at the systemic level, only mild iron overload was observed in the skeletal muscle of HH. Of note, mitochondrial electron transport chain complex I was upregulated in the HH skeletal muscle, which was accompanied by enhanced autophagy. However, these molecular changes were not associated with oxidative stress, suggesting altered mitochondrial metabolism in the muscle in response to iron overload. CONCLUSIONS: These early adaptive responses may be important for supporting mitochondrial health before fully developing skeletal muscle dysfunction in HH. More studies are needed to determine the role of autophagy in the HH-related muscle mitochondrial dysfunction.
Asunto(s)
Hemocromatosis , Sobrecarga de Hierro , Ratones , Animales , Hemocromatosis/genética , Hemocromatosis/complicaciones , Hemocromatosis/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Proteína de la Hemocromatosis/genética , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/complicaciones , Hierro/metabolismo , Ratones Noqueados , Músculo Esquelético/metabolismoRESUMEN
Because of its peculiar redox properties, iron is an essential element in living organisms, being involved in crucial biochemical processes such as oxygen transport, energy production, DNA metabolism, and many others. However, its propensity to accept or donate electrons makes it potentially highly toxic when present in excess and inadequately buffered, as it can generate reactive oxygen species. For this reason, several mechanisms evolved to prevent both iron overload and iron deficiency. At the cellular level, iron regulatory proteins, sensors of intracellular iron levels, and post-transcriptional modifications regulate the expression and translation of genes encoding proteins that modulate the uptake, storage, utilization, and export of iron. At the systemic level, the liver controls body iron levels by producing hepcidin, a peptide hormone that reduces the amount of iron entering the bloodstream by blocking the function of ferroportin, the sole iron exporter in mammals. The regulation of hepcidin occurs through the integration of multiple signals, primarily iron, inflammation and infection, and erythropoiesis. These signals modulate hepcidin levels by accessory proteins such as the hemochromatosis proteins hemojuvelin, HFE, and transferrin receptor 2, the serine protease TMPRSS6, the proinflammatory cytokine IL6, and the erythroid regulator Erythroferrone. The deregulation of the hepcidin/ferroportin axis is the central pathogenic mechanism of diseases characterized by iron overload, such as hemochromatosis and iron-loading anemias, or by iron deficiency, such as IRIDA and anemia of inflammation. Understanding the basic mechanisms involved in the regulation of hepcidin will help in identifying new therapeutic targets to treat these disorders.
Asunto(s)
Hepcidinas , Deficiencias de Hierro , Sobrecarga de Hierro , Hierro , Animales , Hemocromatosis/metabolismo , Hepcidinas/metabolismo , Inflamación , Hierro/metabolismo , Deficiencias de Hierro/metabolismoRESUMEN
The survival, growth, and virulence of Leishmania spp., a group of protozoan parasites, depends on the proper access and regulation of iron. Macrophages, Leishmania's host cell, may divert iron traffic by reducing uptake or by increasing the efflux of iron via the exporter ferroportin. This parasite has adapted by inhibiting the synthesis and inducing the degradation of ferroportin. To study the role of iron in leishmaniasis, we employed Hjv-/- mice, a model of hemochromatosis. The disruption of hemojuvelin (Hjv) abrogates the expression of the iron hormone hepcidin. This allows unrestricted iron entry into the plasma from ferroportin-expressing intestinal epithelial cells and tissue macrophages, resulting in systemic iron overload. Mice were injected with Leishmania major in hind footpads or intraperitoneally. Compared with wild-type controls, Hjv-/- mice displayed transient delayed growth of L. major in hind footpads, with a significant difference in parasite burden 4 weeks post-infection. Following acute intraperitoneal exposure to L. major, Hjv-/- peritoneal cells manifested increased expression of inflammatory cytokines and chemokines (Il1b, Tnfa, Cxcl2, and Ccl2). In response to infection with L. infantum, the causative agent of visceral leishmaniasis, Hjv-/- and control mice developed similar liver and splenic parasite burden despite vastly different tissue iron content and ferroportin expression. Thus, genetic iron overload due to hemojuvelin deficiency appears to mitigate the early development of only cutaneous leishmaniasis.
Asunto(s)
Hemocromatosis , Leishmaniasis Cutánea , Animales , Ratones , Proteínas Ligadas a GPI/metabolismo , Hemocromatosis/genética , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Hierro/metabolismo , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/metabolismo , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/metabolismo , Hígado/metabolismoRESUMEN
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 NoqueadosRESUMEN
Hepcidin is a liver-derived hormone that controls systemic iron traffic. It is also expressed in the heart, where it acts locally. We utilized cell and mouse models to study the regulation, expression, and function of cardiac hepcidin. Hepcidin-encoding Hamp mRNA was induced upon differentiation of C2C12 cells to a cardiomyocyte-like phenotype and was not further stimulated by BMP6, BMP2, or IL-6, the major inducers of hepatic hepcidin. The mRNAs encoding hepcidin and its upstream regulator hemojuvelin (Hjv) are primarily expressed in the atria of the heart, with ~20-fold higher Hamp mRNA levels in the right vs. left atrium and negligible expression in the ventricles and apex. Hjv-/- mice, a model of hemochromatosis due to suppression of liver hepcidin, exhibit only modest cardiac Hamp deficiency and minor cardiac dysfunction. Dietary iron manipulations did not significantly affect cardiac Hamp mRNA in the atria of wild-type or Hjv-/- mice. Two weeks following myocardial infarction, Hamp was robustly induced in the liver and heart apex but not atria, possibly in response to inflammation. We conclude that cardiac Hamp is predominantly expressed in the right atrium and is partially regulated by Hjv; however, it does not respond to iron and other inducers of hepatic hepcidin.
Asunto(s)
Hemocromatosis , Hierro , Ratones , Animales , Hierro/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Hemocromatosis/genética , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Hígado/metabolismo , Atrios Cardíacos/metabolismo , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismoRESUMEN
OBJECTIVES: Arthritis is a common clinical manifestation of hereditary hemochromatosis (HH), and HH is one of a handful of conditions linked to calcium pyrophosphate deposition (CPPD) in joints. The connection between these two types of arthritis has not yet been fully elucidated. In light of new pathogenic pathways recently implicated in CPPD involving bone, we reviewed the literature on the etiology of hemochromatosis arthropathy (HHA) seeking shared pathogenic mechanisms. RESULTS: Clinical observations reinforce striking similarities between HHA and CPPD even in the absence of CPP crystals. They share a similar joint distribution, low grade synovial inflammation, and generalized bone loss. Excess iron damages chondrocytes and bone cells in vitro. While direct effects of iron on cartilage are not consistently seen in animal models of HH, there is decreased osteoblast alkaline phosphatase activity, and increased osteoclastogenesis. These abnormalities are also seen in CPPD. Joint repair processes may also be impaired in both CPPD and HHA. CONCLUSIONS: Possible shared pathogenic pathways relate more to bone and abnormal damage/repair mechanisms than direct damage to articular cartilage. While additional work is necessary to fully understand the pathogenesis of arthritis in HH and to firmly establish causal links with CPPD, this review provides some plausible hypotheses explaining the overlap of these two forms of arthritis.
Asunto(s)
Calcinosis , Cartílago Articular , Condrocalcinosis , Hemocromatosis , Artropatías , Animales , Pirofosfato de Calcio , Cartílago Articular/patología , Condrocalcinosis/patología , Hemocromatosis/complicaciones , Hemocromatosis/genética , Hemocromatosis/metabolismo , Humanos , Hierro/metabolismo , Artropatías/complicacionesRESUMEN
OBJECTIVE: To investigate the effect of Hfe gene mutation on the distribution of iron and periodontal bone loss in periodontal tissues. BACKGROUND DATA: It remains unclear how tissue iron loading affects the periodontium architectures in a genetic animal model of hereditary haemochromatosis (HH). METHODS: Male C57BL/6 Hfe -/- (8 weeks old) and wild-type (WT) mice were utilized to examine the iron distribution in periodontal tissues, as well as periodontal tissues changes using micro-computed tomography and histomorphometric analysis. Furthermore, tissue inflammatory mediators, bone markers and periodontal pathogens were carried out in PFA-fixed paraffin-embedded tissues using ELISA, RT-qPCR and genomic DNA qPCR, respectively. RESULTS: Excessive iron deposition was found in the periodontal ligament, gingiva and alveolar bone in Hfe -/- mice relative to their WT counterparts. This, in turn, was associated with significant periodontal bone loss, increased cemento-enamel junction-alveolar bone crest distance and decreased expression of molecules involved in bone development and turnover. Furthermore, the pro-inflammatory cytokine - interleukin 6 and periodontal bacteria - Campylobacter rectus were significantly increased in Hfe -/- mice compared with WT controls. CONCLUSION: Our results suggest that the iron loading in a mouse model of HH decreases alveolar bone formation and leads to alterations in the inflammatory state in the periodontium. Periodontal health should be assessed during the clinical assessment of HFE-HH patients.
Asunto(s)
Hemocromatosis , Animales , Modelos Animales de Enfermedad , Hemocromatosis/complicaciones , Hemocromatosis/genética , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Hierro/metabolismo , Hígado/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Microtomografía por Rayos XRESUMEN
OBJECTIVES: We developed a natural polyphenol supplement that strongly chelates iron in vitro and assessed its effect on non-heme iron absorption in patients with hereditary hemochromatosis (HH). METHODS: We performed in vitro iron digestion experiments to determine iron precipitation by 12 polyphenol-rich dietary sources, and formulated a polyphenol supplement (PPS) containing black tea powder, cocoa powder and grape juice extract. In a multi-center, single-blind, placebo-controlled cross-over study, we assessed the effect of the PPS on iron absorption from an extrinsically labelled test meal and test drink in patients (n = 14) with HH homozygous for the p.C282Y variant in the HFE gene. We measured fractional iron absorption (FIA) as stable iron isotope incorporation into erythrocytes. RESULTS: Black tea powder, cocoa powder and grape juice extract most effectively precipitated iron in vitro. A PPS mixture of these three extracts precipitated ~ 80% of iron when 2 g was added to a 500 g iron solution containing 20 µg Fe/g. In the iron absorption study, the PPS reduced FIA by ~ 40%: FIA from the meal consumed with the PPS was lower (3.01% (1.60, 5.64)) than with placebo (5.21% (3.92, 6.92)) (p = 0.026)), and FIA from the test drink with the PPS was lower (10.3% (7.29 14.6)) than with placebo (16.9% (12.8 22.2)) (p = 0.002). CONCLUSION: Our results indicate that when taken with meals, this natural PPS can decrease dietary iron absorption, and might thereby reduce body iron accumulation and the frequency of phlebotomy in patients with HH. TRIAL REGISTRY: clinicaltrials.gov (registration date: 9.6.2019, NCT03990181).
Asunto(s)
Hemocromatosis , Adulto , Estudios Cruzados , Hemocromatosis/tratamiento farmacológico , Hemocromatosis/genética , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Hierro , Hierro de la Dieta , Polifenoles/farmacología , Polvos , Método Simple Ciego , TéRESUMEN
The protein HFE (homeostatic iron regulator) is a key regulator of iron metabolism, and mutations in HFE underlie the most frequent form of hereditary haemochromatosis (HH-type I). Studies have shown that HFE interacts with transferrin receptor 1 (TFR1), a homodimeric type II transmembrane glycoprotein that is responsible for the cellular uptake of iron via iron-loaded transferrin (holo-transferrin) binding. It has been hypothesised that the HFE/TFR1 interaction serves as a sensor to the level of iron-loaded transferrin in circulation by means of a competition mechanism between HFE and iron-loaded transferrin association with TFR1. To investigate this, a series of peptides based on the helical binding interface between HFE and TFR1 were generated and shown to significantly interfere with the HFE/TFR1 interaction in an in vitro proximity ligation assay. The helical conformation of one of these peptides, corresponding to the α1 and α2 helices of HFE, was stabilised by the introduction of sidechain lactam "staples", but this did not result in an increase in the ability of the peptide to disrupt the HFE/TFR1 interaction. These peptides inhibitors of the protein-protein interaction between HFE and TFR1 are potentially useful tools for the analysis of the functional role of HFE in the regulation of hepcidin expression.
Asunto(s)
Hemocromatosis , Hepcidinas , Hemocromatosis/genética , Hemocromatosis/metabolismo , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Hepcidinas/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Hierro/metabolismo , Lactamas , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Péptidos/metabolismo , Péptidos/farmacología , Receptores de Transferrina/metabolismo , Transferrina/metabolismoRESUMEN
The discovery of hepcidin has provided a solid foundation for understanding the mechanisms of systemic iron homeostasis and the aetiologies of iron disorders. Hepcidin assures the balance of circulating and stored iron levels for multiple physiological processes including oxygen transport and erythropoiesis, while limiting the toxicity of excess iron. The liver is the major site where regulatory signals from iron, erythropoietic drive and inflammation are integrated to control hepcidin production. Pathologically, hepcidin dysregulation by genetic inactivation, ineffective erythropoiesis, or inflammation leads to diseases of iron deficiency or overload such as iron-refractory iron-deficiency anaemia, anaemia of inflammation, iron-loading anaemias and hereditary haemochromatosis. In the present review, we discuss recent insights into the molecular mechanisms governing hepcidin regulation, how these pathways are disrupted in iron disorders, and how this knowledge is being used to develop novel diagnostic and therapeutic strategies.
Asunto(s)
Anemia Ferropénica , Eritropoyesis , Hemocromatosis , Hepcidinas , Hígado , Anemia Ferropénica/genética , Anemia Ferropénica/metabolismo , Anemia Ferropénica/patología , Anemia Ferropénica/fisiopatología , Animales , Hemocromatosis/genética , Hemocromatosis/metabolismo , Hemocromatosis/patología , Hemocromatosis/fisiopatología , Hepcidinas/sangre , Hepcidinas/genética , Humanos , Hígado/metabolismo , Hígado/patología , Hígado/fisiopatologíaRESUMEN
Iron is fundamental for several biological functions, but when in excess can lead to the development of toxic events. Some tissues and cells are more susceptible than others, but systemic iron levels can be controlled by treating patients with iron-chelating molecules and phlebotomy. An early diagnostic can be decisive to limit the progression of musculoskeletal complications like osteoarthritis and osteoporosis because of iron toxicity. In iron-related osteoarthritis, aggravation can be associated to a few events that can contribute to joints articular cartilage exposure to high iron concentrations, which can promote articular degeneration with very little chance of tissue regeneration. In contrast, bone metabolism is much more dynamic than cartilage, but progressive iron accumulation and ageing can be decisive factors for bone health. The iron overload associated with hereditary diseases like hemochromatosis, hemophilias, thalassemias and other hereditary anaemias increase the negative impact of iron toxicity in joints and bone, as well as in life quality, even when iron levels can be controlled. The molecular mechanisms by which iron can compromise cartilage and bone have been illusive and only in the last 20 years studies have started to shed some light into the molecular mechanisms associated with iron toxicity. Ferroptosis and the regulation of intracellular iron levels is instrumental in the balance between detoxification and induced cell death. In addition, these complications are accompanied with multiple susceptibility factors that can aggravate iron toxicity and should be identified. Therefore, understanding tissues microenvironment and cell communication is fundamental to contextualize iron toxicity.
Asunto(s)
Hemocromatosis/metabolismo , Sobrecarga de Hierro/metabolismo , Hierro/metabolismo , Osteoartritis/metabolismo , Animales , Proteínas de Transporte de Catión/metabolismo , Hemocromatosis/complicaciones , Hepcidinas/metabolismo , Humanos , Sobrecarga de Hierro/complicaciones , Modelos Biológicos , Osteoartritis/complicaciones , Transferrina/metabolismoRESUMEN
Accumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.
Asunto(s)
Hemocromatosis/patología , Cuerpos de Lewy/patología , Enfermedades por Almacenamiento Lisosomal/patología , Enfermedades Mitocondriales/patología , alfa-Sinucleína/metabolismo , Hemocromatosis/metabolismo , Humanos , Cuerpos de Lewy/metabolismo , Metabolismo de los Lípidos/fisiología , Enfermedades por Almacenamiento Lisosomal/metabolismo , Lisosomas/metabolismo , Lisosomas/patología , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/metabolismoRESUMEN
ß-thalassemias result from mutations in ß-globin, causing ineffective erythropoiesis and secondary iron overload due to inappropriately low levels of the iron regulatory hormone hepcidin. Mutations in transferrin receptor 2 (TFR2) lead to hereditary hemochromatosis (HH) as a result of inappropriately increased iron uptake from the diet, also due to improperly regulated hepcidin. TFR2 is also thought to be required for efficient erythropoiesis through its interaction with the erythropoietin receptor in erythroid progenitors. Transmembrane serine protease 6 (TMPRSS6), a membrane serine protease expressed selectively in the liver, participates in regulating hepcidin production in response to iron stores by cleaving hemojuvelin (HJV). We have previously demonstrated that inhibiting TMPRSS6 expression with a hepatocyte-specific siRNA formulation, induces hepcidin, mitigates anemia, and reduces iron overload in murine models of ß-thalassemia intermedia and HH. Here, we demonstrate that Tmprss6 siRNA treatment of double mutant Tfr2Y245X/Y245X HH Hbbth3/+ thalassemic mice induces hepcidin and diminishes tissue and serum iron levels. Importantly, treated double mutant animals produce more mature red blood cells and have a nearly 50% increase in hemoglobin compared to untreated ß-thalassemic mice. Furthermore, we also show that treatment of Tfr2Y245X/Y245X HH mice leads to increased hepcidin expression and reduced total body iron burden. These data indicate that siRNA suppression of Tmprss6, in conjunction with the targeting of TFR2, may be superior to inhibiting Tmprss6 alone in the treatment of the anemia and secondary iron loading in ß-thalassemia intermedia and may be useful as a method of suppressing the primary iron overload in TFR2-related (type 3) hereditary hemochromatosis.
Asunto(s)
Hemocromatosis/metabolismo , Deficiencias de Hierro , Receptores de Transferrina/deficiencia , Talasemia beta/metabolismo , Sustitución de Aminoácidos , Animales , Modelos Animales de Enfermedad , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Hemocromatosis/genética , Hemocromatosis/patología , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Mutación Missense , Receptores de Transferrina/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Talasemia beta/genética , Talasemia beta/patologíaRESUMEN
AIM: To define reference values for the transverse relaxation rate (R2∗) in iron storage organs and to investigate the role of human haemochromatosis protein (HFE) genotype on iron storage. MATERIALS AND METHODS: Whole-body magnetic resonance imaging (MRI) including a five-echo gradient-echo sequence was performed in 483 volunteers (269 men, mean age 59.3 ± 12.2 years) without clinical evidence of an iron storage disease at 1.5 T. R2∗ values were assessed for liver, spleen, pancreas, heart, bones, and brain parenchyma. The HFE genotype was determined regarding the single nucleotide polymorphisms (SNPs) rs74315324, rs1799945, rs41303501, rs1800562, rs1800730. R2∗ values were compared among participants without and with at least one mutation. R2∗ reference values were defined using volunteers without any mutation. RESULTS: Three hundred and one participants had no mutations in any HFE SNP, 182 had at least one mutation. HFE gene mutations were distributed as (heterozygous/homozygous) rs1799945:132/9, rs1800562:33/1, and rs1800730:11/0. Mean R2∗ values ± SD (per second) in the group without mutation were: liver: 33.4 ± 12.7, spleen: 24.1 ± 13.8, pancreas: 27.2 ± 6.6, heart: 32.7 ± 11.8, bone: 69.3 ± 21.0, brain parenchyma: 13.9 ± 1.2. No significant difference in R2∗ values were found between participants with and without the HFE gene mutation for any examined iron storage organ (pliver=0.09, pspleen=0.36, ppancreas = 0.08, pheart = 0.36, pbone = 0.98, pbrain=0.74). CONCLUSION: Reference values of R2∗ in iron storage organs are feasible to support the diagnosis of iron storage diseases. Non-specific mutations in HFE SNPs appear not to affect the phenotype of tissue iron accumulation.
Asunto(s)
Proteína de la Hemocromatosis/genética , Hemocromatosis/diagnóstico , Hierro/metabolismo , Imagen por Resonancia Magnética/métodos , Polimorfismo de Nucleótido Simple/genética , Imagen de Cuerpo Entero/métodos , Estudios de Cohortes , Femenino , Genotipo , Alemania , Hemocromatosis/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
Hereditary hemochromatosis (HH) is mostly caused by mutations in the iron-regulatory gene HFE. The disease is associated with iron overload, resulting in liver cirrhosis/cancer, cardiomegaly, kidney dysfunction, diabetes, and arthritis. Fe2+-induced oxidative damage is suspected in the etiology of these symptoms. Here we examined, using Hfe-/- mice, whether disruption of uric acid (UA) homeostasis plays any role in HH-associated arthritis. We detected elevated levels of UA in serum and intestine in Hfe-/- mice compared with controls. Though the expression of xanthine oxidase, which generates UA, was not different in liver and intestine between wild type and Hfe-/- mice, the enzymatic activity was higher in Hfe-/- mice. We then examined various transporters involved in UA absorption/excretion. Glut9 expression did not change; however, there was an increase in Mrp4 and a decrease in Abcg2 in Hfe-/- mice. As ABCG2 mediates intestinal excretion of UA and mutations in ABCG2 cause hyperuricemia, we examined the potential connection between iron and ABCG2. We found p53-responsive elements in hABCG2 promoter and confirmed with chromatin immunoprecipitation that p53 binds to this promoter. p53 protein was reduced in Hfe-/- mouse intestine. p53 is a heme-binding protein and p53-heme complex is subjected to proteasomal degradation. We conclude that iron/heme overload in HH increases xanthine oxidase activity and also promotes p53 degradation resulting in decreased ABCG2 expression. As a result, systemic UA production is increased and intestinal excretion of UA via ABCG2 is decreased, causing serum and tissue accumulation of UA, a potential factor in the etiology of HH-associated arthritis.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Hemocromatosis/metabolismo , Hiperuricemia/enzimología , Ácido Úrico/metabolismo , Xantina Oxidasa/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Animales , Femenino , Hemocromatosis/complicaciones , Hemocromatosis/congénito , Hemocromatosis/enzimología , Proteína de la Hemocromatosis/genética , Proteína de la Hemocromatosis/metabolismo , Homeostasis , Humanos , Hiperuricemia/etiología , Hiperuricemia/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Xantina Oxidasa/genéticaRESUMEN
Hereditary hemochromatosis (HH), an iron-overload disease, is a prevalent genetic disorder. As excess iron causes a multitude of metabolic disturbances, we postulated that iron overload in HH disrupts colonic homeostasis and colon-microbiome interaction and exacerbates the development and progression of colonic inflammation and colon cancer. To test this hypothesis, we examined the progression and severity of colitis and colon cancer in a mouse model of HH (Hfe-/-), and evaluated the potential contributing factors. We found that experimentally induced colitis and colon cancer progressed more robustly in Hfe-/- mice than in wild-type mice. The underlying causes were multifactorial. Hfe-/- colons were leakier with lower proliferation capacity of crypt cells, which impaired wound healing and amplified inflammation-driven tissue injury. The host/microflora axis was also disrupted. Sequencing of fecal 16S RNA revealed profound changes in the colonic microbiome in Hfe-/- mice in favor of the pathogenic bacteria belonging to phyla Proteobacteria and TM7. There was an increased number of bacteria adhered onto the mucosal surface of the colonic epithelium in Hfe-/- mice than in wild-type mice. Furthermore, the expression of innate antimicrobial peptides, the first-line of defense against bacteria, was lower in Hfe-/- mouse colon than in wild-type mouse colon; the release of pro-inflammatory cytokines upon inflammatory stimuli was also greater in Hfe-/- mouse colon than in wild-type mouse colon. These data provide evidence that excess iron accumulation in colonic tissue as happens in HH promotes colitis and colon cancer, accompanied with bacterial dysbiosis and loss of function of the intestinal/colonic barrier.
Asunto(s)
Colitis , Neoplasias del Colon , Disbiosis , Microbioma Gastrointestinal , Hemocromatosis , Proteobacteria/crecimiento & desarrollo , Animales , Colitis/genética , Colitis/metabolismo , Colitis/microbiología , Colitis/patología , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/microbiología , Neoplasias del Colon/patología , Disbiosis/genética , Disbiosis/metabolismo , Disbiosis/microbiología , Disbiosis/patología , Hemocromatosis/genética , Hemocromatosis/metabolismo , Hemocromatosis/microbiología , Hemocromatosis/patología , Proteína de la Hemocromatosis/deficiencia , Proteína de la Hemocromatosis/metabolismo , Ratones , Ratones Noqueados , Proteobacteria/clasificaciónRESUMEN
Iron overload induces intestinal-permeability defect (gut leakage), and gut translocation of organismal molecules might enhance systemic inflammation and sepsis severity in patients with thalassemia (Thal). Hence, iron administration in Hbbth3/+ mice, heterozygous ß-globin-deficient Thal mice, was explored. Oral iron administration induced more severe secondary hemochromatosis and gut leakage in Thal mice compared with wild-type (WT) mice. Gut leakage was determined by 1) FITC-dextran assay, 2) spontaneous serum elevation of endotoxin (LPS) and (1â3)-ß-d-glucan (BG), molecular structures of gut-organisms, and 3) reduction of tight-junction molecules with increased enterocyte apoptosis (activated caspase-3) by immunofluorescent staining. Iron overload also enhanced serum cytokines and increased Bacteroides spp. (gram-negative bacteria) in feces as analyzed by microbiome analysis. LPS injection in iron-overloaded Thal mice produced higher mortality and prominent cytokine responses. Additionally, stimulation with LPS plus iron in macrophage from Thal mice induced higher cytokines production with lower ß-globin gene expression compared with WT. Furthermore, possible gut leakage as determined by elevated LPS or BG (>60 pg/mL) in serum without systemic infection was demonstrated in 18 out of 41 patients with ß-thalassemia major. Finally, enhanced LPS-induced cytokine responses of mononuclear cells from these patients compared with cells from healthy volunteers were demonstrated. In conclusion, oral iron administration in Thal mice induced more severe gut leakage and increased fecal gram-negative bacteria, resulting in higher levels of endotoxemia and serum inflammatory cytokines compared with WT. Preexisting hyperinflammatory cytokines in iron-overloaded Thal enhanced susceptibility toward infection.NEW & NOTEWORTHY Although the impact of iron accumulation in several organs of patients with thalassemia is well known, the adverse effect of iron accumulation in gut is not frequently mentioned. Here, we demonstrated iron-induced gut-permeability defect, impact of organismal molecules from gut translocation of, and macrophage functional defect upon the increased sepsis susceptibility in thalassemia mice.