(LB03-06-25) A New Nutritional Paradigm to Investigate Mechanisms of Heme-iron Absorption in Rats and Mice

Objectives: Heme iron (HI), derived principally from hemoglobin (Hb) present in animal products, is an excellent source of dietary iron for humans; however, despite more than 60 years of research, molecular mechanisms of HI absorption are largely unknown. Previous work established that laboratory rats could absorb and utilize dietary ion derived from heme, but efficiency varied highly between studies. Moreover. the generalized perception in the field is that mice are poor absorbers of HI, so useful mouse models of this process are currently lacking. We sought to develop new rodent models of HI absorption, which could ultimately be used to test the roles of candidate transporters and enzymes via genetic engineering technology.

Methods: Sprague-Dawley (SD) rats and C57BL/6 (B6) were fed AIN-93-based, HI-enriched experimental diets that were formulated with lyophilized porcine red blood cells (85% HI and 15% nonheme iron [NHI]). Precisely matched control diets contained NHI as ferrous sulfate. Experiments aimed to test the ability of HI to provide adequate iron to correct iron-deficiency anemia, support pregnancy, and drive iron loading in hepcidin KO rats and mice (modeling hereditary hemochromatosis).

Results: Consumption of HI or NHI diets with 50-75 ppm total iron effectively resolved iron-deficiency anemia and supported pregnancy and neonatal development in Sprague-Dawley rats and also, unexpectedly, in C57BL/6 mice. Moreover, hepcidin-KO SD rats and B6 mice, absorbed excess dietary iron and developed iron overload when consuming a HI or a NHI diet.

Conclusions: These studies have demonstrated that a HI diet supports recovery from IDA, and pregnancy and development of neonates in SD rats and B6 mice. Dietary HI also contributes to iron loading in hepcidin KOs. Different results may have been obtained in the current study due to our unique approach of including HI as porcine RBCs in the context of semi-purified, defined rodent diets. Identifying appropriate rat and mouse strains and defining a nutritional/physiological paradigm in which to study HI absorption should provide new opportunities to experimentally address fundamental uncertainties in this important area of research.

Funding Sources: This investigation was supported by grants R01DK074867, R01DK109717, R56DK137863, and R01DK134583.