Iron is an essential nutrient, yet it is toxic in excess. Since humans have no regulated means to rid the body of excess iron, overall body levels reflect absorption of dietary iron in the proximal small bowel. After ferrous iron (Fe2+) is absorbed into duodenal enterocytes, efflux by ferroportin 1 (Fpn1) is functionally coupled to iron oxidation, to allow ferric iron (Fe3+) to bind to transferrin (Tf) in the interstitial fluids. This oxidation is presumed to be accomplished by the ferroxidase (FOX) hephaestin (Heph), but recent studies from our group have demonstrated that additional intestinal FOXs exist. Furthermore, the requirement for enzymatic iron oxidation is unclear since the interstitial fluids contain dissolved oxygen. The preponderance of evidence, however, suggests that enzymatic iron oxidation is most likely required, especially when iron demand increases. My studies were designed to test the hypothesis that intestinal Heph is required for iron absorption only under conditions in which iron requirements increase, including postnatal growth, iron deficiency/hypoxia, acute hemolytic stress, pregnancy and lactation. To test this hypothesis, I utilized 2 distinct, complementary models: 1) male and female mice lacking Heph only in the intestine (and littermate controls); and 2) human intestinal epithelial (Caco-2) cells with normal or diminished Heph expression. The experimental approach was designed not only to test the essentiality of Heph, but also to lay the groundwork for future studies aimed at identifying novel intestinal ferroxidases (FOXs). Results showed that intestinal Heph was indeed required for optimal iron absorption in male and female rapidly growing neonatal mice and also in pregnant mice. In adult mice of both sexes subjected to dietary iron restriction or acute hemolysis and in lactating female mice, however, lack of intestinal Heph was without consequence. The in vitro studies with Caco-2 cells showed that Heph was not required for optimal iron absorption, at least under the experimental conditions that I utilized. Overall, this investigation has provided novel evidence regarding the essentiality of intestinal Heph under different physiologic conditions and has provided the impetus for future studies related to novel intestinal (or circulating) FOXs and their roles in intestinal iron absorption. 15
|Advisor:||Collins, James F.|
|Commitee:||Knutson, Mitchell D., Nelson, Corwin D., Percival, Susan S.|
|School:||University of Florida|
|School Location:||United States -- Florida|
|Source:||DAI-B 79/04(E), Dissertation Abstracts International|
|Keywords:||copper absorption, hephaestin, iron deficiency, iron regulation|
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