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Title: Regulation of intestinal iron transport and storage proteins by body iron stores and the implications for the control of iron absorption
Author: Chua, Edward Soon Kheng
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1997
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This thesis sets out to examine how body iron stores may influence mucosal cell handling of dietary iron. It is proposed that transferrin receptors (TfR) located at the basolateral surface of the enterocytes serve to 'inform' mucosal cells regarding body iron stores. It is further postulated that mucosal crypt cells can only influence mucosal handling of dietary iron after they have migrated to their final destination at the terminal villus architecture: a 'lag period' of some 3-5 days. This concept of a 'lag period' stem from previous iron absorption studies where changes in body iron stores required a period of some 3-5 days before mucosal cells were able to 'respond' to changes in dietary iron. A re-evaluation of the 'mucosal block' hypothesis was undertaken using recent molecular biological techniques with TfR at the basolacteral surface of enterocytes serving to 'inform' these cells regarding body iron stores. This information imparted to the enterocytes in turn sets up a specific L:H ferritin transcript ratio in the crypt cells. As these cells migrate to the terminal villus, ferritin mRNA translation will produce a specific heteroploymer protein that will either impede or facilitate iron transfer to the portal circulation based on ferritin L:H transcript ratios predetermined by body iron stores in crypt cells some 3 days earlier. To examine this hypothesis, an adaptation of a previously described method of separating crypt and villus cells was undertaken. These studies revealed a reciprocal relationship between TfR and body iron stores such that when body iron stores were depleted, TfR expression was enhanced to facilitate iron entry to cells. However, when body iron stores become replete, TfR expression were downregulated to reduce iron entry to cells. Dietary manipulation revealed that mucosal cell ferritin transcripts responded to changes in luminal iron, but this response was observed in both crypt and villus cells within 24 hours of dietary manipulation and did not follow the proposed lag period of 3-5 days corresponding to crypt-villus cell migration. Mucosal ferritin transcripts were also examined in subjects with primary iron overload i.e. genetic haemochromatosis (GH). A method of separating crypt and villus cells in the human intestinal mucosa had not been previously described and this technique was developed denovo. Mucosal ferritin expression were significantly lower in subjects with GH when compared to control subjects with normal iron stores. This observation is consistent with enhanced iron transfer to portal blood and probably does not indicate a defect in ferritin expression in subjects with GH.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available