scholarly journals Iron homeostasis in a mouse model of thalassemia intermedia is altered between adolescence and adulthood

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8802
Author(s):  
Chanita Sanyear ◽  
Punnee Butthep ◽  
Wiraya Eamsaard ◽  
Suthat Fucharoen ◽  
Saovaros Svasti ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mrna Expression ◽  
Iron Homeostasis ◽  
Pathological Condition ◽  
Iron Status ◽  
Age Groups ◽  
Reticuloendothelial System ◽  
Growth Spurt ◽  
Thalassemia Intermedia ◽  
Hemoglobin Metabolism

Background Iron overload is one of common complications of β-thalassemia. Systemic iron homeostasis is regulated by iron-regulatory hormone, hepcidin, which inhibits intestinal iron absorption and iron recycling by reticuloendothelial system. In addition, body iron status and requirement can be altered with age. In adolescence, iron requirement is increased due to blood volume expansion and growth spurt. Heterozygous β-globin knockout mice (Hbbth3/+; BKO) is a mouse model of thalassemia widely used to study iron homeostasis under this pathological condition. However, effects of age on iron homeostasis, particularly the expression of genes involved in hemoglobin metabolism as well as erythroid regulators in the spleen, during adolescence have not been explored in this mouse model. Methods Iron parameters as well as the mRNA expression of hepcidin and genes involved in iron transport and metabolism in wildtype (WT) and BKO mice during adolescence (6–7 weeks old) and adulthood (16–20 weeks old) were analyzed and compared by 2-way ANOVA. Results The transition of adolescence to adulthood was associated with reductions in duodenal iron transporter mRNA expression and serum iron levels of both WT and BKO mice. Erythrocyte parameters in BKO mice remained abnormal in both age groups despite persistent induction of genes involved in hemoglobin metabolism in the spleen and progressively increased extramedullary erythropiesis. In BKO mice, adulthood was associated with increased liver hepcidin and ferroportin mRNA expression along with splenic erythroferrone mRNA suppression compared to adolescence. Conclusion Our results demonstrate that iron homeostasis in a mouse model of thalassemia intermedia is altered between adolescence and adulthood. The present study underscores the importance of the age of thalassemic mice in the study of molecular or pathophysiological changes under thalassemic condition.

scholarly journals Sensing of Liver Iron Content Requires Cell-Cell Communication between Hepatocytes and Liver Sinusoidal Endothelial Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 432-432
Author(s):  
Silvia Colucci ◽  
Sandro Altamura ◽  
Matthias Hentze ◽  
Martina U. Muckenthaler
Keyword(s):  
Endothelial Cells ◽  
Mrna Expression ◽  
Iron Content ◽  
Iron Homeostasis ◽  
Iron Status ◽  
Molecular Signature ◽  
Iron Release ◽  
Liver Sinusoidal Endothelial Cells ◽  
Intracellular Iron ◽  
Sinusoidal Endothelial Cells

The liver stores iron and senses systemic and tissue iron availability. Hepatocytes control iron homeostasis by producing the peptide hormone hepcidin that controls dietary iron absorption and iron release from intracellular stores. Recent data challenged the exclusive role of hepatocytes in controlling iron levels. Indeed, liver sinusoidal endothelial cells (LSECs) increase BMP2 and BMP6 levels in response to iron, which control hepcidin expression in a paracrine manner. However the molecular mechanism(s) of how BMPs respond to iron levels remain unknown. We established primary murine LSEC cultures and exposed these to iron sources. Unexpectedly, BMP2 mRNA expression is strongly reduced by iron treatment, while BMP6 levels are only mildly increased. This finding suggests that intracellular iron content cannot directly activate BMP2 transcription and only slightly contribute to BMP6 upregulation in LSEC cultures. However, if LSECs are co-cultured with iron-loaded primary hepatocytes the expression of BMP2 and BMP6 is increased and the fold induction of BMP6 is greater compared to LSECs cultured alone, suggesting that the iron status of hepatocytes instructs the LSEC BMP response. These data are supported by findings in a genetic mouse model of iron overload (Slc40a1C326S/C326S). Hepatocytes isolated from Slc40a1C326S/C326S mice display an iron-loaded molecular signature and the expected low mRNA expression of Transferrin Receptor 1 (Tfr1). By contrast, LSECs show high expression of Tfr1, indicating intracellular iron deficiency. Despite this, hepatic BMP levels are increased, suggesting that BMP2 and BMP6 expression are directly related to the intracellular iron content of hepatocytes but not LSECs. RNA-sequencing of isolated hepatic cell populations is ongoing to identify putative hepatocyte regulators involved in the iron-mediated BMP2 and BMP6 regulation. Disclosures Muckenthaler: Silence Therapeutics: Consultancy; Novartis: Research Funding.

The Iron Status of Canadian Adolescents and Adults: Current Knowledge and Practical Implications

2006 ◽  
Vol 67 (3) ◽  
pp. 130-138 ◽  
Author(s):  
Marcia J. Cooper ◽  
Kevin A. Cockell ◽  
Mary R. L’abbé
Keyword(s):  
Work Performance ◽  
Current Knowledge ◽  
Iron Status ◽  
Age Groups ◽  
Reproductive Age ◽  
Physical Work ◽  
Growth Spurt ◽  
Dietary Iron ◽  
Teenage Girls ◽  
Adverse Pregnancy

Overview: Iron is an essential nutrient, playing a central role in oxygen transport and cellular energy metabolism. The importance of ensuring adequate bioavailable dietary iron stems from the severe consequences associated with iron deficiency (ID) and anemia, including reduced immune function and resistance to infection, developmental delays and irreversible cognitive deficits in young children, impaired physical work performance, and adverse pregnancy outcomes. Specific populations: Poor dietary iron intake and ID exist in Canada, particularly in women of reproductive age. Data from the provincial nutrition surveys suggest that the prevalence of inadequate iron intakes (and low intakes of absorbable iron) among women under 50 years of age is over 10%, which may reflect poor iron status. Teenage girls are at risk for low iron stores because of the adolescent growth spurt and the onset of menstruation; those who are vegetarian are at even greater risk. Conclusions: The Canadian diet has changed so that grain products are now the main source of dietary iron for all age groups. The public must be educated to ensure the consumption of adequate quantities of bioavailable iron and enhancing factors such as vitamin C. Industry, government, and health professionals must work together to promote healthy eating patterns and the selection of appropriate foods.

scholarly journals CBIO-10. REDUCED IRON EXPORT FUNCTIONS IN A CELL INTRINSIC MANNER TO DRIVE GLIOBLASTOMA GROWTH

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii17-ii17
Author(s):  
Katie Troike ◽  
Erin Mulkearns-Hubert ◽  
Daniel Silver ◽  
James Connor ◽  
Justin Lathia
Keyword(s):  
Tumor Cells ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Status ◽  
Tumor Grade ◽  
Hfe Gene ◽  
Iron Release ◽  
Female Patients ◽  
Cellular Iron

Abstract Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is characterized by invasive growth and poor prognosis. Iron is a critical regulator of many cellular processes, and GBM tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving tumor initiation and growth. While iron uptake has been the central focus of previous investigations, additional mechanisms of iron regulation, such as compensatory iron efflux, have not been explored in the context of GBM. The hemochromatosis (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by limiting cellular iron release, resulting in a sequestration phenotype. We find that HFE is upregulated in GBM tumors compared to non-tumor brain and that expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. Based on these findings, we hypothesize that GBM tumor cells upregulate HFE expression to augment cellular iron loading and drive proliferation, ultimately leading to reduced survival of female patients. To test this hypothesis, we generated Hfe knockdown and overexpressing mouse glioma cell lines. We observed significant alterations in the expression of several iron handling genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. Additionally, we show that knockdown of Hfe in these cells increases apoptosis and leads to a significant impairment of tumor growth in vivo. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression. Future work will include further exploration of the mechanisms that contribute to these phenotypes as well as interactions with the tumor microenvironment. Elucidating the mechanisms by which iron effulx contributes to GBM may inform the development of next-generation targeted therapies.

scholarly journals Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia

2016 ◽  
Vol 8 (5) ◽  
pp. 517-528 ◽  
Author(s):  
Andrew E. Armitage ◽  
Pei Jin Lim ◽  
Joe N. Frost ◽  
Sant-Rayn Pasricha ◽  
Elizabeth J. Soilleux ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Brucella Abortus ◽  
Serum Iron ◽  
Vibrio Vulnificus ◽  
Iron Status ◽  
Transgenic Mouse Model ◽  
Innate Immune ◽  
Serum Hepcidin

Withdrawal of iron from serum (hypoferraemia) is a conserved innate immune antimicrobial strategy that can withhold this critical nutrient from invading pathogens, impairing their growth. Hepcidin (Hamp1) is the master regulator of iron and its expression is induced by inflammation. Mice lacking Hamp1 from birth rapidly accumulate iron and are susceptible to infection by blood-dwelling siderophilic bacteria such as Vibrio vulnificus. In order to study the innate immune role of hepcidin against a background of normal iron status, we developed a transgenic mouse model of tamoxifen-sensitive conditional Hamp1 deletion (termed iHamp1-KO mice). These mice attain adulthood with an iron status indistinguishable from littermate controls. Hamp1 disruption and the consequent decline of serum hepcidin concentrations occurred within hours of a single tamoxifen dose. We found that the TLR ligands LPS and Pam3CSK4 and heat-killed Brucella abortus caused an equivalent induction of inflammation in control and iHamp1-KO mice. Pam3CSK4 and B. abortus only caused a drop in serum iron in control mice, while hypoferraemia due to LPS was evident but substantially blunted in iHamp1-KO mice. Our results characterise a powerful new model of rapidly inducible hepcidin disruption, and demonstrate the critical contribution of hepcidin to the hypoferraemia of inflammation.

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