Intestinal Iron Transport in Iron Deficiency/Anemia

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DESCRIPTION (provided by applicant): Intestinal iron absorption is mediated by several proteins that have only recently been identified. However, several lines of experimental pursuit have suggested that there are other unknown genes involved in this important physiological process. Thus, we performed comparative gene chips studies designed to identify changes in the expression of known and unknown genes involved in iron transport in the duodenal mucosa of anemic rats at 8 days, 21 days, 6 weeks, 12 and 26-weeks-of-age. Our results demonstrate changes in gene expression that are unique at the different ages, but we also found that certain genes change across all age groups studied. We found that among iron transport genes, only the genes encoding the brush-border membrane proteins dcytb and DMT1 were consistently induced in anemia, while other genes involved in iron export from enterocytes such as ferroportin and hephaestin did not show changes in the iron deficient state. Interestingly however, we found consistent upregulation of genes that have not been described to be involved in iron transport in the mammalian duodenum. These changes include 4-12-fold upregulation of the basolateral membrane-specific copper ATPase (Atp7a), and 2-5-fold increases in a membrane bound form of ceruloplasmin, a multi-copper ferroxidase, which was seen in adult rats. As the brush-border membrane copper transporter Ctrl did not change expression levels, we suggest that copper may enter enterocytes via DMT1. There is a well-known link between copper and iron homeostasis as copper deficiency causes anemia and iron deficiency anemia leads to increased body copper levels. From these findings, we hypothesize that chronic iron deficiency leads to compensatory increases in the expression of brush-border iron transport proteins dcytb and DMT1 (which may also transport copper), increased basolateral export of copper via the copper ATPase, and increased expression of GPI-anchored ceruloplasmin, all of which may work in concert to enhance body iron delivery. In order to explore this possibility, we plan to pursue the following Specific AIMS: 1) decipher transcriptional regulation of dcytb and DMT1 by iron, and 2) characterize basolateral copper ATPase activity and protein expression in iron deficiency and characterize expression of membrane-associated ceruloplasmin in the duodenum of iron deficient rats. Overall, these studies will likely lead to increased understanding of the interplay between intestinal iron absorption and body copper homeostasis and will explore the role of GPI-anchored ceruloplasmin in intestinal iron transport.