Genetic Model of iron deficiency in the Mouse Liver
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE86292 | GEO | 2018/02/13
REPOSITORIES: GEO
Similar Datasets
Project description:Iron overload causes the generation of reactive oxygen species, which can lead to lasting damage to the liver and other organs. We studied the effects of iron deficiency and iron overload on the hepatic transcriptional and metabolomic profile in mouse models.
2018-02-13 | GSE86236 | GEO
Project description:Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin (Hamp), a hepatic-derived hormone that controls iron mobilization through its molecular target, ferroportin (FPN), the only known mammalian iron exporter. Here, we took a transcriptomic approach to to compare the duodenal transcriptome during systemic iron demand to that of hepcidin-deficiency iron overload. Hampfl/fl (control) and AlbCreERT2;Hampfl/fl mice were placed on iron-replete and low-iron diets and were sacrificed two weeks following tamoxifen treatment. Duodenum RNA expression was compared across genotypes and across iron-replete and low iron diets.
2018-12-12 | E-MTAB-7329 | biostudies-arrayexpress
Project description:In plasma, iron is normally bound to transferrin, but in conditions of iron overload when the iron-binding capacity of transferrin is exceeded, non-transferrin-bound iron (NTBI) appears in plasma. NTBI is taken up by hepatocytes and other parenchymal cells via NTBI transporters and can cause cellular damage by promoting the generation of reactive oxygen species. However, how NTBI affects endothelial cells, the most proximal cell type exposed to circulating NTBI, has not been explored. We modeled in vitro the effects of systemic iron overload on endothelial cells by treating primary human umbilical vein endothelial cells (HUVECs) with NTBI (ferric ammonium citrate, FAC). Using an unbiased approach, we showed by RNA-Seq that iron loading alters lipid homeostasis in HUVECs by inducing SREBP2-mediated cholesterol biosynthesis. We also determined that FAC increased the susceptibility of HUVECs to apoptosis induced by TNFα. Moreover, we showed that cholesterol biosynthesis contributes to iron-potentiated apoptosis. Treating HUVECs with a cholesterol chelator hydroxypropyl-β-cyclodextrin demonstrated that depletion of cholesterol was sufficient to rescue HUVECs from TNFa-induced apoptosis, even in the presence of FAC. Finally, we showed that FAC or cholesterol treatment modulated the TNFα pathway by inducing novel proteolytic processing of TNFR1 to a short isoform that localizes to lipid rafts. Our study raises the possibility that iron-mediated toxicity in human iron overload disorders is at least in part dependent on alterations in cholesterol metabolism in endothelial cells, increasing their susceptibility to apoptosis.
2021-09-01 | GSE168534 | GEO
Project description:Hereditary Hemochromatosis (HH) is an autosomal recessive disorder characterized by an abnormally low expression or functional derangement of the iron regulatory hormone hepcidin. The absorption of dietary iron is disproportionate in these patients, leading to iron deposition in several tissues and consequent damage of organs including liver, heart, and pancreas. Late complications in absence of diagnosis and treatment include cirrhosis, hepatocellular carcinoma, cardiomyopathy and diabetes. Unfortunately, iron overload appears also as an acquired complication. This is the case of a variety of anemias (thalassemias, myelodysplastic syndromes, hemoglobinopathies, etc.) in which compensating mechanisms increase iron absorption. Another cause of iron overload in these patients are the repeated transfusional treatments they receive. It follows that iron overload is a common clinical problem. Therefore, we investigated the effects of iron overload on gene expression in skeletal muscle and heart using microarray technology. Genes with up-regulated expression after iron overload in both skeletal and heart muscle included angiopoietin-like 4, pyruvate dehydrogenase kinase 4 and calgranulin A and B. The expression of transferrin receptor, heat shock protein 1B and DnaJ homolog B1 were down-regulated by iron in both muscle types. Two potential hepcidin regulatory genes, hemojuvelin and neogenin, showed no clear change in expression after iron overload. Concluding, microarray analysis revealed iron-induced changes in the expression of several genes involved in the regulation of glucose and lipid metabolism, transcription and cellular stress responses. These may represent novel connections between iron overload and pathological manifestations of HH such as cardiomyopathy and diabetes. Keywords: iron induced stress response
2007-11-30 | GSE9726 | GEO
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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2013-11-27 | BIOMD0000000498 | BioModels
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.
2023-05-03 | GSE186655 | GEO
Project description:Microvascular endothelial cells (EC) display a high degree of phenotypic and functional heterogeneity among different organs. Organ-specific EC control their tissue microenvironment by angiocrine factors in health and disease. Liver sinusoidal EC (LSEC) are uniquely differentiated to fulfil important organ-specific functions in development, under homeostatic conditions, and in regeneration and liver pathology. Recently, Bmp2 has been identified by us as an organ-specific angiokine derived from LSEC. To study angiocrine Bmp2 signaling in the liver, we conditionally deleted Bmp2 in LSEC using EC subtype-specific Stab2-Cre mice. Genetic inactivation of hepatic angiocrine Bmp2 signaling in Stab2-Cre;Bmp2fl/fl (Bmp2LSECKO) mice caused massive iron overload in the liver, and increased serum iron levels and iron deposition in several organs similar to classic hereditary hemochromatosis. Iron overload was mediated by decreased hepatic expression of hepcidin, a key regulator of iron homeostasis. Thus, angiocrine Bmp2 signaling within the hepatic vascular niche represents a constitutive pathway indispensable for iron homeostasis in vivo that is non-redundant with Bmp6. Notably, we demonstrate that organ-specific angiocrine signaling is essential not only for the homeostasis of the respective organ, but also for the homeostasis of the whole organism.
2017-01-31 | GSE90506 | GEO
Project description:Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues leading to eventual organ failure. We have discovered a novel mechanism to reverse iron overload by pharmacological modulation of the divalent metal transporter-1 (DMT-1). DMT-1 mediates intracellular iron transport during the transferrin cycle and apical iron absorption in the duodenum. Additional functions in iron handling in the kidney and liver are less well understood. We show that the L- type calcium-channel blocker nifedipine increases DMT-1 mediated cellular iron transport 10-to 100-fold at concentrations between 1-100 uM. Mechanistically, nifedipine causes this effect by prolongation of the activity of DMT-1 to transport iron. We show that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload, and enhances urinary iron excretion. Modulation of DMT-1 function by L-type calcium-channel blockers emerges a novel pharmacological concept to treat iron overload disorders.<br> <br> In this experiment mice were subjected to dietary iron overload before being treated with nifedipine at 5 ug/g bodyweight, or mock treated with the same volume of solvent.
2007-03-01 | E-MEXP-982 | biostudies-arrayexpress
Project description:Tissue iron (Fe) overload is a frequent pathologic finding in multiple disease states including non-alcoholic fatty liver disease (NAFLD), neurodegenerative disorders, cardiomyopathy, diabetes, and some forms of cancer. The role of iron, as a cause or consequence of disease progression and observed phenotypic manifestations, remains controversial. In addition, the impact of genetic variation on iron overload related phenotypes is unclear, and the identification of genetic modifiers is incomplete. Here, our aim was to characterize the genetic architecture of dietary iron overload and pathology using the Hybrid Mouse Diversity Panel (HMDP), a panel of over 100 genetically distinct mouse strains optimized for genome-wide association studies and systems genetics. Dietary iron overload was induced by feeding male mice (114 strains, 6-7 mice per strain on average) a high iron diet for six weeks, and then tissues were collected at 10-11 weeks of age. Liver metal levels and gene expression were measured by ICP-MS and RNASeq, and lipids were measured by colorimetric assays. FaST-LMM was used for genetic mapping, and Metascape, WGCNA, and Mergeomics were used for pathway, module, and key driver bioinformatics analyses. Mice on the high Fe diet accumulated Fe in the liver, with a 6.5-fold difference across strain means. The iron loaded diet also led to a spectrum of copper deficiency and anemia, with liver copper levels highly correlated with red blood cell count, hemoglobin, and hematocrit. Hepatic steatosis of various severity was observed histologically, with 52.5-fold variation in triglyceride (TG) levels across the strains. TG and Fe mapped most significantly to an overlapping locus on chromosome 7 that has not been previously associated with either trait. Based on network modeling, significant key drivers for both Fe and TG accumulation are involved in cholesterol biosynthesis and oxidative stress management. To make the full data set accessible and useable by others, we have made our data and analyses available on a resource website.
2023-08-11 | GSE230674 | GEO
Project description:Microarray analysis of pancreatic tissue comparing gene expression in rats fed an iron deficient or iron loaded diet vs. iron adequate diet. Goal was to determine changes in gene expression in response to iron status. 2 separate two-condition experiments: iron deficient (FeD) vs. iron adequate (FeA), and iron overload (FeO) vs. iron adequate (FeA). Performed in dye-switched duplicates. Samples pooled (n=6).
2013-02-27 | E-GEOD-44699 | biostudies-arrayexpress