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1 Steele Memorial Children's Research Center, Department of Pediatrics, University of Arizona, Tucson, AZ, USA; Steele Memorial Children's Research Center, Department of Nutritional Sciences, University of Arizona, Tucson, AZ, USA
2 Steele Memorial Children's Research Center, Department of Pediatrics, University of Arizona, Tucson, AZ, USA
3 Department of Medicine and Division of Gastroenterology, University of Washington Medical Center, Seattle, WA, USA
* To whom correspondence should be addressed. E-mail: jcollins{at}peds.arizona.edu.
We sought to identify novel genes involved in intestinal iron absorption by inducing iron-deficiency in groups of rats during post-natal development from the suckling period through adulthood. We then performed comparative gene chip analyses (Affymetrix; RAE230A and RAE230B chips) with cRNA derived from duodenal mucosa. Real-time PCR was used to confirm changes in gene expression. Genes encoding the apical iron transport-related proteins (DMT1 and Dcytb) were strongly induced at all ages studied, while increases in mRNA encoding the basolateral proteins IREG1 and hephaestin were observed only by real-time PCR. In addition, transferrin receptor 1 and heme oxygenase 1 were also induced. We also identified induction of novel genes not previously associated with intestinal iron transport. The Menkes copper ATPase (ATP7a) and metallothionein were strongly induced at all ages studied, suggesting increased copper absorption by enterocytes during iron-deficiency. We also found significantly increased liver copper levels in 7- to 12-week-old iron-deficient rats. Also upregulated at most ages examined were the sodium-dependent vitamin C transporter, tripartite motif protein 27, aquaporin 4, lipocalin-interacting membrane receptor and the breast cancer-resistance protein (ABCG2). Some genes also showed decreased expression with iron-deprivation, including several membrane transporters, metabolic enzymes and genes involved in the oxidative stress response. We speculate that dietary iron-deprivation leads to increased intestinal copper absorption via DMT1 on the brush-border membrane and the Menkes copper ATPase on the basolateral membrane. These findings may thus explain copper loading in the iron-deficient state. We also demonstrate that many other novel genes may be differentially regulated in the setting of iron-deprivation.
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