Masison2022 - Liver Iron Metabolism with updated ferritin
Ontology highlight
ABSTRACT:
SUBMITTER: 
Pedro Mendes
PROVIDER: MODEL2211030002 | BioModels | 2023-02-07
REPOSITORIES: BioModels
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| MODEL2211030002?filename=LiverIronMetabolism_UpdatedFerritin.cps | Other | |||
| MODEL2211030002?filename=LiverIronMetabolism_UpdatedFerritin_sbml_l3v1.xml | Xml |
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Project description:Mitchell2013 - Liver Iron Metabolism
The model includes the core regulatory components of human liver iron metabolism.
This model is described in the article:
A computational model of liver iron metabolism.
Mitchell S, Mendes P.
PLoS Comput. Biol. 2013 Nov; 9(11): e1003299
Abstract:
Iron is essential for all known life due to its redox properties; however, these same properties can also lead to its toxicity in overload through the production of reactive oxygen species. Robust systemic and cellular control are required to maintain safe levels of iron, and the liver seems to be where this regulation is mainly located. Iron misregulation is implicated in many diseases, and as our understanding of iron metabolism improves, the list of iron-related disorders grows. Recent developments have resulted in greater knowledge of the fate of iron in the body and have led to a detailed map of its metabolism; however, a quantitative understanding at the systems level of how its components interact to produce tight regulation remains elusive. A mechanistic computational model of human liver iron metabolism, which includes the core regulatory components, is presented here. It was constructed based on known mechanisms of regulation and on their kinetic properties, obtained from several publications. The model was then quantitatively validated by comparing its results with previously published physiological data, and it is able to reproduce multiple experimental findings. A time course simulation following an oral dose of iron was compared to a clinical time course study and the simulation was found to recreate the dynamics and time scale of the systems response to iron challenge. A disease state simulation of haemochromatosis was created by altering a single reaction parameter that mimics a human haemochromatosis gene (HFE) mutation. The simulation provides a quantitative understanding of the liver iron overload that arises in this disease. This model supports and supplements understanding of the role of the liver as an iron sensor and provides a framework for further modelling, including simulations to identify valuable drug targets and design of experiments to improve further our knowledge of this system.
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2024-09-02 | BIOMD0000000498 | BioModels
Project description:The mycobacterial IdeR protein is a metal-dependent regulator of the DtxR (diphtheria toxin repressor) family. In the presence of iron, it binds to a specific DNA sequence in the promoter regions of the genes that it regulates, thus controlling their transcription. In this study, we provide evidence that ideR is an essential gene in Mycobacterium tuberculosis. ideR cannot normally be disrupted in this mycobacterium in the absence of a second functional copy of the gene. However, a rare ideR mutant was obtained in which the lethal effects of ideR inactivation were alleviated by a second-site suppressor mutation and which exhibited restricted iron assimilation capacity. Studies of this strain and a derivative in which IdeR expression was restored allowed us to identify phenotypic effects resulting from ideR inactivation. Using DNA microarrays, the iron-dependent transcriptional profiles of the wild-type, ideR mutant, and ideR complemented mutant strains were analyzed, and the genes regulated by iron and IdeR were identified. These genes encode a variety of proteins, including putative transporters, proteins involved in siderophore synthesis and iron storage, members of the PE/PPE family, a membrane protein involved in virulence, transcriptional regulators, and enzymes involved in lipid metabolism. Keywords: strain or line design, genetic modification design, comparative genome hybridization design and stimulus or stress design 18 samples were analyzed. The quality controls were biological replicate and technical replicate
2007-08-08 | E-GEOD-8732 | biostudies-arrayexpress
Project description:The mycobacterial IdeR protein is a metal-dependent regulator of the DtxR (diphtheria toxin repressor) family. In the presence of iron, it binds to a specific DNA sequence in the promoter regions of the genes that it regulates, thus controlling their transcription. In this study, we provide evidence that ideR is an essential gene in Mycobacterium tuberculosis. ideR cannot normally be disrupted in this mycobacterium in the absence of a second functional copy of the gene. However, a rare ideR mutant was obtained in which the lethal effects of ideR inactivation were alleviated by a second-site suppressor mutation and which exhibited restricted iron assimilation capacity. Studies of this strain and a derivative in which IdeR expression was restored allowed us to identify phenotypic effects resulting from ideR inactivation. Using DNA microarrays, the iron-dependent transcriptional profiles of the wild-type, ideR mutant, and ideR complemented mutant strains were analyzed, and the genes regulated by iron and IdeR were identified. These genes encode a variety of proteins, including putative transporters, proteins involved in siderophore synthesis and iron storage, members of the PE/PPE family, a membrane protein involved in virulence, transcriptional regulators, and enzymes involved in lipid metabolism. Keywords: strain or line design, genetic modification design, comparative genome hybridization design and stimulus or stress design
2007-08-09 | GSE8732 | GEO
Project description:Liver iron overload can induce hepatic expression of hepcidin and regulates iron metabolism. However, the mechanism of iron regulating iron metabolism remains known. Intracellular labile iron represents the nonferritin-bound, redox-active iron which is transitory and serves as a crossroad of cell iron metabolism. The role of intracellular labile iron played in iron metabolism has largely been elucidated. Here we show that intracellular labile iron of hepatocytes has dual function in iron metabolism. It can induce hepatocytes expressing hepcidin via ER stress induced transcription factors on the one hand, on the other hand stimulate BMP2 and BMP6 expression of liver sinusoidal endothelial cells (LSECs) though TNFα secreted by hepatocytes to further regulate iron metabolism. Blockade of TNFα could dysregulate the iron metabolism during iron overload. Our findings reveal the important role of intracellular labile iron in iron metabolism and represent a novel way to modulate iron metabolism during iron overload.
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Project description:Iron induces hepcidin by activating bone morphogenetic protein (BMP)6-SMAD signaling, which is critical for regulation of systemic iron homeostasis. High iron levels induce BMP6 production in liver endothelial cells, but the molecular mechanisms by which iron regulates BMP6 are incompletely understood. To address this, we performed RNA-sequencing on sorted liver endothelial cells from iron-adequate and iron-loaded mice.
2023-12-25 | GSE223871 | GEO
Project description:Iron is an essential nutritional element; its deficiency in the body causes nutritional problems and a decrease in iron storage that can lead to anemia. The liver not only stores iron but is an important metabolic target as well. Dietary iron deficiency is associated with changes in the metabolism of nutrients such as lipids. However, to the best of our knowledge, a global analysis detailing the consequences of iron deficiency in the body has not yet been reported. We performed a comprehensive transcriptome analysis using DNA microarray technology to reveal the effects of iron deficiency on hepatic gene expression. Four-week-old rats were fed an iron-deficient diet or a control diet for 16 days. On day 17, the rats were sacrificed under anesthesia, and their livers were dissected for DNA microarray analysis. We identified 600 up-regulated and 500 down-regulated probe sets to characterize the iron-deficient diet group. The up-regulated probe sets contained genes for enzymes that are involved in cholesterol, amino acid, and glucose metabolisms, as well as in apoptosis. The down-regulated probe sets included genes for enzymes associated with lipid metabolism. Additionally, the 16-day iron-deficient diet induced anemia. Our gene expression analysis revealed that, as a result, cholesterol biosynthesis, gluconeogenesis, and apoptosis due to endoplasmic reticulum stress were accelerated, while fatty acid biosynthesis was suppressed by dietary iron deficiency. Our analysis also showed that cholesterol metabolism, including bile acid biosynthesis, was accelerated in the initial stages of cholesterol accumulation. Experiment Overall Design: Male 3-week-old Sprague Dawley rats were purchased from Charles River Japan (Kanagawa, Japan) and housed in a room conditioned at 24 ± 1°C and 40 ± 5% humidity with a 12-h light-dark cycle (lights on at 08:00). The rats were given a control diet and water for 24 h ad libitum. Diets for rats were obtained from Research Diets, Inc. (New Brunswick, NJ, USA). The composition of the control diet was based on the AIN93G diet , except that cellulose was replaced by Avicel, since cellulose is an ingredient of variable iron content. The iron-deficient diet was prepared by removal of iron (ferric citrate) from the control diet. At day 8, rats were divided into two groups comprising animals of similar body weights. One group (n = 6) was fed the control diet and the other group (n = 7) was fed the iron-deficient diet (iron-deficient diet group). After iron-deficient diet feeding was started, blood hemoglobin levels were measured every two days. Blood samples for hemoglobin measurements were collected from the tail vein, and hemoglobin levels were measured by using the Wako Hemoglobin B test (Wako Pure Chemical Industries, Osaka, Japan). On day 12 of the iron-deficient diet treatment, diets were removed at 17:00, and feeding was conducted between 09:00 and 17:00 for another 4 days. This protocol was intended to synchronize the ratsâ feeding behavior. On day 17 of the iron-deficient diet treatment, rats were fed for 1.5 h prior to sacrifice under anesthesia. Livers were then excised and subsequently immersed in RNAlater (Applied Biosystems Japan, Tokyo, Japan). Blood hemoglobin level of rats fed an iron-deficient diet decreased significantly over the course of the feeding. On day 17, the hemoglobin level in the iron-deficient diet group was 42% of that of the control diet group (P < 0.01).
2009-07-11 | E-GEOD-16899 | biostudies-arrayexpress
Project description:All living cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here, we report a universal eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of genes encoding high-affinity leucine transporters and RAPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency (ID) supersedes other nutrient inputs into mTORC1. This process occurs in vivo, and is not an indirect effect by canonical iron-utilizing pathways. Elevated expression of KDM3B targets is associated with reduced survival in a subset of human cancers and ID represses mTORC1 in patient-derived tumor cells and sensitizes cancer cells to chemotherapy. These data demonstrate a novel mechanism of eukaryotic iron sensing through dynamic chromatin remodeling and repression of mTORC1 mediated anabolism. Due to ancestral eukaryotes sharing homologues of KDMs and mTORC1 core components, this pathway likely predated the emergence of the other kingdom-specific nutrient sensors for mTORC1
2023-07-18 | GSE214019 | GEO
Project description:Iron metabolism has emerged as a critical factor in cell viability, both in normal and pathological contexts. However, the intricate relationship between iron metabolism and the maintenance of adult stem cells and cancer stem cells remains incompletely understood. The ferritin complex, responsible for intracellular iron storage and buffering, plays a pivotal role in this process. Our research provides insights into the regulatory role of ferritin-mediated iron homeostasis in hematopoietic stem cells (HSCs).
2024-04-17 | GSE240742 | GEO
Project description:In the alpha subclass of proteobacteria iron homeostasis is controlled by diverse iron responsive regulators. Caulobacter crescentus, an important freshwater α-proteobacterium, uses the ferric uptake repressor (Fur) for such purpose. However, the impact of the iron availability on the C. crescentus transcriptome and an overall perspective of the regulatory networks involved remain unknown. In this work we report the identification of iron-responsive and Fur-regulated genes in C. crescentus using microarray-based global transcriptional analyses. We identify 46 genes that were strongly upregulated both by mutation of fur and by iron limitation condition. Among them, there are genes involved in iron uptake (four TonB dependent receptor gene clusters, feoAB), riboflavin biosynthesis and some genes encoding hypothetical proteins. Most of these genes are associated with Fur binding sites, implicating them as direct targets of Fur-mediated repression. These data were validated by β-galactosidase and EMSA assays for two operons encoding putative transporters. The role of Fur as a positive regulator is also evident, given that 50 genes were downregulated both by mutation of fur and under low-iron condition. As expected, this group includes many genes involved in energy metabolism, mostly iron-using enzymes. Surprisingly, are also included in this group many genes encoding TonB dependent receptors and the genes fixK, fixT and ftrB encoding an oxygen signaling network required for growth during hypoxia. Bioinformatics analyses performed in the promoters of these genes suggest that positive regulation by Fur is mainly indirect. In addition to the Fur modulon, iron limitation altered expression of more 103 genes, including upregulation of genes involved in Fe-S cluster assembly, oxidative stress and heat shock response, as well as downregulation of genes implicated in amino acid metabolism, chemotaxis and motility. Altogether, our results showed that adaptation of C. crescentus to iron limitation involves increasing the transcription of iron-acquisition systems and decreasing the production of iron-using proteins as a general strategy Two experimental procedures, each of them performed in two replicates. A total of four independent biological samples were used
2013-08-15 | E-GEOD-45653 | biostudies-arrayexpress
Project description:Leptospirosis is a globally significant zoonotic disease caused by Leptospira spp. Iron is essential for growth of most bacterial species. Since availability of iron is low in the host, pathogens have evolved complex iron acquisition mechanisms to survive and establish infection. Virulence genes in some bacteria have been shown to be iron-regulated. In many bacteria, expression of iron-uptake and storage proteins is regulated by Fur. L. interrogans encodes four predicted Fur homologs; we have constructed a mutant in one of these, la1857. We conducted microarray analysis to identify differentially expressed genes in L. interrogans serovar Manilae grown under low iron compared with normal iron conditions found in EMJH medium. We also compared the transcriptional profile of the la1857 mutant versus wild-type Manilae under normal and low iron conditions.
2010-03-22 | GSE20422 | GEO