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Biochemical, Molecular, and Genetic Mechanisms

Belgrade Rats Display Liver Iron Loading¹

² Department of Genetics and Complex Diseases and ³ Department of Environmental Health, Harvard School of Public Health, Boston, MA, 02115

^* To whom correspondence should be addressed. E-mail: wessling{at}hsph.harvard.edu.

Patients with mutations in divalent metal transporter-1 (DMT1), an intestinal nonheme iron transporter, suffer from microcytic anemia and hepatic iron loading. DMT1 is also mutated in Belgrade rats, an animal model with a thalassemic-like disorder of microcytic anemia with hyperferrinemia. However, aspects of hepatic iron loading in this genetic model are not well characterized. To more fully define the Belgrade rat's iron status, we compared the characteristics of homozygous (b/b) and heterozygous (b/+) rats fed an iron-supplemented diet for 3 wk postweaning. Dietary supplementation with ferrous iron improved the anemia of b/b rats insofar as hematocrits increased from 0.13 (21-d–old) to 0.31 (42-d–old). However, hematocrits remained significantly lower than those of age-matched b/+ rats (0.36 and 0.41 in 21- and 42-d–old heterozygotes, respectively, P < 0.05). Wright's staining of b/b red cells confirmed the hypochromic microcytic nature of Belgrade rats' anemia. The liver iron concentration of 42-d–old b/b rats was greater than in age-matched b/+ rats (5.97 vs. 2.24 µmol/g, P < 0.05). Whereas Perls' Prussian blue iron staining was evident in both periportal and centrilobular regions in 42-d–old b/b liver sections, no staining was observed in age-matched b/+ tissue sections. Quantitative real-time PCR analysis showed that expression of liver hepcidin mRNA in 42-d–old b/b rats was 3-fold greater than age-matched b/+ rats. These results indicate that, similar to human patients with DMT1 mutations, Belgrade rats also display hepatic iron loading. Our data suggest this condition arises from ineffective erythropoiesis.

This article has been cited by other articles:

				K. Thompson, R. M. Molina, T. Donaghey, J. D. Brain, and M. Wessling-Resnick Iron absorption by Belgrade rat pups during lactation Am J Physiol Gastrointest Liver Physiol, September 1, 2007; 293(3): G640 - G644. [Abstract] [Full Text] [PDF]