Iron regulatory protein as an endogenous sensor of iron in rat intestinal mucosa

Abstract

Duodenal enterocytes adjust intestinal iron absorption to the body's state of iron repletion. Here we tested how iron supply from the blood modulates the RNA-binding activity of iron regulatory proteins (IRP-1 and IRP-2) in immature duodenal rat enterocytes, and whether the modulation is compatible with the hypothesis that IRPs, in turn, may regulate the expression of iron transport proteins in maturating enterocytes during migration to the villus tips. Tissue uptake of parenterally applied 59 Fe along the duodenal crypt±villus axis was compared to local IRP-1 and IRP-2 activity and to duodenal 59 Fe transport capacity 12 h, 48 h, and 72 h after intravenous iron administration to iron-deficient rats. IRP-1 and IRP-2 activity was significantly increased in iron-deficiency. 59Fe administrated from the blood side was almost exclusively taken up by crypt enterocytes. Accordingly, the activity of IRP-1 decreased at this site 12 h after parenteral iron administration, but remained high at the villus tips. After 48 h the bulk of 59 Fe containing enterocytes had migrated to the villus tips. Correspondingly, IRP-1 activity was decreased at duodenal villus tips after 48 h. IRP-2 activity also tended to decrease, though the change was statistically not significant. IRP-2 activity remained significantly higher at duodenal villus tips than in crypts, even after 72 h. Intestinal iron absorption capacity decreased with the same delay as IRP-1 activity after intravenous iron administration. In the ileum 59 Fe uptake from the blood and IRP activity showed no significant difference between crypt and villus region. Luminal administration of iron decreased duodenal IRP-1 and IRP-2 activity at tips and crypts within 2 h. Thus, recently absorbed iron becomes available to cytosolic IRP during its passage through the enterocyte. Our results are compatible with a role of IRPs in gearing the expression of intestinal iron transporters in the duodenal brushborder to the body's state of iron repletion.

Extra-mitochondrial localisation of frataxin and its association with IscU1 during enterocyte-like differentiation of the human colon adenocarcinoma cell line Caco-2

“…The mature enterocytes are specialised for absorption and transport of iron and differ from the undifferentiated precursors in their expression of iron uptake and iron transport proteins (Ekmekcioglu et al, 1998;Griffiths et al, 2000). Undifferentiated cells can be considered as sensors of body iron requirement responding to serum iron levels (Schumann et al, 1999;Morgan and Oates, 2002). Upon differentiation, enterocytes become able to transport iron, and Fe/S-iron regulatory proteins (IRPs) play a central role in the regulation of the enterocytes' iron uptake machinery.…”

Serum ceruloplasmin protein expression and activity increases in iron-deficient rats and is further enhanced by higher dietary copper intake

“…For pPD assay, the gel was briefly rinsed in water, incubated in 30 mL of 0.1% pPD in 0.1M CH 3 COONa-CH 3 COOH buffer, pH 5.0, for 2-3 hours in the dark with gentle shaking, rinsed in MilliQ water (Millipore), and air-dried overnight in a gel-frame. For Fz assay, the gel was incubated in 200M Fe(NH 4 ) 2 (SO 4 ) 2 (H 2 O) 6 in 0.1M CH 3 COONa-CH 3 COOH buffer, pH 5.0, for 2-3 hours in the dark with gentle orbital shaking. After rinsing with MilliQ water, the gel was reacted with 15mM Fz solution, and color development was allowed to proceed.…”

“…Several key genes encoding iron transport-related proteins are strongly induced during iron deprivation, [3][4][5] some by posttranscriptional stabilization of mRNA transcripts, 6 and others via transcriptional induction mediated at least in part by a hypoxia-responsive trans-acting factor, hypoxia-inducible factor (HIF) 2␣. 7,8 In addition, genes related to intestinal copper homeostasis are induced during iron deprivation in rats, 4,9 suggesting that copper is important in the physiologic response of the intestinal epithelium to iron deficiency.…”

Hereditary hemochromatosis: update for 2003

“…The complex of TfR-1 and apotransferrin then recycles back to the basolateral surface where apotransferrin is released at the higher extracellular pH [7]. The concentration of intracellular iron in duodenal crypt cells may play an important role in programming the eventual expression of DMT-1 and ferroportin 1 in daughter enterocytes [50,51]. This regulation may occur at the level of mRNA translation through the action of the iron regulatory protein/iron responsive element system, or at the level of gene transcription [51].…”