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Masison2024 - Enterocyte Iron Mucosal Block

ABSTRACT: Enterocyte Iron Mucosal Block This is a model of enterocyte iron absorption, consisting of iron uptake (movement of iron from intestinal lumen into cytplasm), and transfer (transport of iron from cytoplasm to blood/plasma). The model was created by Joseph Masison and Pedro Mendes. Intestinal mucosal block is a cellular phenomenon defined by a transient reduction in iron absorption by intestinal epithelial cells following previous iron exposures. Understanding what controls the mucosal block is central to understanding how intestinal iron absorption contributes to pathological iron states. Three mechanisms implicated in driving mucosal block are the endocytosis of divalent metal transporter 1 (DMT1), sequestration of iron by cytosolic ferritin, and iron regulatory proteins (IRPs) regulation of ferritin expression. Here, we build a model that reproduces the mucosal block phenomena, based on published experimental data, and use it to quantify the contribution of each mechanism to the block. Model analysis shows ferritin and IRPs regulation have the largest quantitative impact on the mucosal block. Lastly, DMT1 endocytosis is shown to play a role in limiting total enterocyte iron uptake, protecting the cell against oxidative stress, but does not contribute to the decrease in total iron transfer seen in mucosal block. CC0 1.0 Universal: To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. You can copy, modify, distribute and perform the work, even for commercial purposes, all without asking permission. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Pedro Mendes

PROVIDER: MODEL2405170001 | BioModels | 2025-02-11

REPOSITORIES: BioModels

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			Action	DRS
	MODEL2405170001?filename=Masison2024_EnterocyteIronMucosalBlock.cps	Other
	MODEL2405170001?filename=Masison2024_EnterocyteIronMucosalBlock.xml	Xml

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Project description:Iron is essential for all cells but is toxic in excess, so iron absorption and distribution are tightly regulated. Serum iron is bound to transferrin and primarily enters erythroid cells via receptor-mediated endocytosis of the transferrin receptor (Tfr1). Tfr1 is essential for developing erythrocytes and reduced Tfr1 expression is associated with anemia. The transcription factors STAT5A/B are activated by many cytokines, including erythropoietin. Stat5a/b-/- mice are severely anemic and die perinatally, but no link has been made to iron homeostasis. To study the function of STAT5A/B in vivo, we deleted the floxed Stat5a/b locus in hematopoietic cells with a Tie2-Cre transgene. These mice exhibited microcytic, hypochromic anemia, as did lethally irradiated mice transplanted with Stat5a/b-/- fetal liver cells. Flow cytometry and RNA analyses of erythroid cells from mutant mice revealed a 50% reduction in Tfr1 mRNA and protein. We detected STAT5A/B binding sites in the first intron of the Tfr1 gene and found that expression of constitutively active STAT5A in an erythroid cell line increased Tfr1 levels. Chromatin immunoprecipitation experiments confirmed the binding of STAT5A/B to these sites. We conclude that STAT5A/B is an important regulator of erythroid progenitor iron uptake via its control of Tfr1 transcription. Experiment Overall Design: Isolated Ter119-positive fetal liver cells from three to five E14.5 embryos of the same genotype were combined, and total RNA was extracted using TRIzol reagent (Life Technologies) with two additional ethanol precipitations. RNA quality was verified using an Agilent Bioanalyzer (Agilent Technologies). Microarray analyses were performed using Affymetrix Mouse Genome 430 2.0 array GeneChips (Affymetrix). Up- and down-regulated genes were selected based on P values of <0.05 and fold changes of >1.5 or -1.5 as assessed by ANOVA using Partek Pro software (Partek). To determine specific pathways, gene pathway analysis was obtained using the statistically significant gene list (P<0.05) represented on the chip.

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Masison2024 - Enterocyte Iron Mucosal Block

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