Delayed hepcidin response explains the lag period in iron absorption following a stimulus to increase erythropoiesis (original) (raw)

Delayed hepcidin response explains the lag period in iron absorption following a stimulus to increase erythropoiesis

D M Frazer1,*,
H R Inglis1,*,
S J Wilkins1,
K N Millard1,
T M Steele1,
G D McLaren2,
A T McKie3,
C D Vulpe4,
G J Anderson1
1Iron Metabolism Laboratory, the Queensland Institute of Medical Research and the University of Queensland, PO Royal Brisbane Hospital, Brisbane, Queensland, Australia
2Division of Haematology/Oncology, University of California, Irvine, Irvine, California, USA, and VA Long Beach Healthcare System, Long Beach, California, USA
3Division of Life Sciences, King’s College, London, UK
4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California, USA
Correspondence to:
Dr G J Anderson
Iron Metabolism Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane Queensland 4029, Australia; gregAqimr.edu.au

Abstract

Introduction: The delay of several days between an erythropoietic stimulus and the subsequent increase in intestinal iron absorption is commonly believed to represent the time required for body signals to programme the immature crypt enterocytes and for these cells to migrate to the villus. Recent data however suggest that signals from the body to alter absorption are mediated by circulating hepcidin and that this peptide exerts its effect on mature villus enterocytes.

Methods: We have examined the delay in the absorptive response following stimulated erythropoiesis using phenylhydrazine induced haemolysis and correlated this with expression of hepcidin in the liver and iron transporters in the duodenum.

Results: There was a delay of four days following haemolysis before a significant increase in iron absorption was observed. Hepatic hepcidin expression did not decrease until day 3, reaching almost undetectable levels by days 4 and 5. This coincided with the increase in duodenal expression of divalent metal transporter 1, duodenal cytochrome b, and Ireg1.

Conclusion: These results suggest that the delayed increase in iron absorption following stimulated erythropoiesis is attributable to a lag in the hepcidin response rather than crypt programming, and are consistent with a direct effect of the hepcidin pathway on mature villus enterocytes.

APR, acute phase response
DAB, 3,3′-diamino-benzidine
Dcytb, duodenal cytochrome b
DMT1, divalent metal transporter 1
GAPDH, glyceraldehyde-3-phosphate dehydrogenase
IRE, iron responsive element
PBS, phosphate buffered saline
PHZ, phenylhydrazine
RE, reticuloendothelial
RPA, ribonuclease protection assay
TfR1, transferrin receptor 1
TfR2, transferrin receptor 2
divalent metal transporter 1
DMT1
duodenal cytochrome b
Dcytb
Ireg1
iron absorption
erythropoiesis
hepcidin

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