Molecular Mechanisms of Intestinal Iron Transport
Sponsored by the APS Gastrointestinal & Liver Physiology Section

The overall control of iron homeostasis occurs at the transport step in the epithelium of the proximal small bowel, where absorption is precisely regulated to match body iron losses. Iron-deficiency anemia and hereditary hemochromatosis (HH; e.g. iron overload) are common clinical entities in the U.S., in which perturbed intestinal iron transport occurs. Thus, a detailed understanding of the molecular mechanisms of intestinal iron transport and its regulation is critical to develop therapeutic interventions for these and other common pathological states related to iron metabolism. Our first speaker, Kris V. Kowdley, M.D., an expert in the phenotypical aspects of human, iron-related pathophysiologies, will describe perturbations in intestinal iron transport seen in patients with HH and iron deficiency. Recent studies have identified several proteins involved in intestinal iron absorption, including the brush-border proteins divalent metal-ion transporter 1 (DMT1) and duodenal cytochrome b (DCYTB), and the basolateral-specific proteins hephaestin  (HP) and iron-regulated gene 1 (IREG1). The genes encoding these proteins are known to be strongly induced by dietary iron deprivation, and in some cases this occurs via post-transcriptional mechanisms, although transcriptional events may also be important. DMT1 was cloned by expression cloning in Xenopus oocytes and has been shown to transport a number of divalent metal ions in addition to iron. DMT1 is also known to have alternatively spliced transcripts that may affect protein activity and regulation by body iron status. Our second speaker, Bryan Mackenzie, Ph.D. will provide new information regarding the functional aspects of DMT1, derived mainly from in vitro expression studies in Xenopus oocytes. That DMT1 is critical for adequate absorption of non-heme iron is demonstrated by the iron-deficient phenotype of Belgrade rats (b), which have a point mutation in the DMT1 gene that perturbs membrane trafficking of the protein to the plasma membrane. Our third speaker, Michael D. Garrrick, Ph.D. will focus on a wealth of molecular studies using the Belgrade rat model. And finally, our fourth speaker, Marianne Wessling-Resnick, Ph.D., will provide experimental information regarding molecular mechanisms of iron extrusion from intestinal epithelial cells as mediated by the IREG1 protein. Recent investigations have revealed that intestinal iron transport can be regulated at multiple levels by the antimicrobial protein hepcidin, which is produced and secreted by the liver in response to several physiological cues. By offering a balance of in vivo and in vitro models, our symposium speakers will provide our audience with cutting-edge insight into the molecular mechanisms of intestinal iron transport and its regulation in various pathological states.  With both the recent molecular identification of the major components of the iron-absorptive machinery, and novel insight into the action of hepcidin, this symposium will offer a very timely perspective into this rapidly-progressing and important field of scientific pursuit.