Brain iron uptake in hypotransferrinemic mice: Influence of systemic iron status

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The relationship of the heterogeneity of iron concentrations in the brain with the regulation of iron uptake into specific brain regions remains unresolved. We used hypotransferrinemic mice and an iron-deficient or control diet to explore whether plasma transferrin (Tf), transferrin saturation, and plasma iron levels influence the uptake of (59)Fe and whether there was brain region specificity. Weaning wild-type (+/+) and heterozygotic mice (+/hpx), were sorted randomly to either a iron-deficient diet or a control iron diet for 8 weeks, whereas homozygous mice (hpx/hpx) ate the control diet for 8 weeks before (59)Fe uptake studies. Iron-deficient heterozygous and wild-type mice both had significantly greater plasma Tf levels (37.5 and 42.5 microM) than control mice had (heterozygous and wild-type controls were 20 and 32.5 microM) and far more than homozygous mice (<0.2 microM) had, thus providing five distinct levels of plasma Tf concentrations. After intravenous injection of (59)Fe, brains of iron-deficient wild-type mice took up significantly more (59)Fe (0.15% dose) compared to control wild-type mice (0.056%) at 2 hr, a treatment effect that persisted through 24 hr. In contrast, diet had no effect in heterozygous mice. Importantly, homozygous mice had equivalent uptake to other groups (0.089% dose) by 24 hr. Early brain radioactivity varied by regions (hypothalamus and prefrontal cortex approximately 10-18% brain uptake > cerebellum, pons, thalamus, and striatum approximately 7-12% > cortex, hippocampus, and substantia nigra approximately 6-8%). This distribution of radioactivity changed over 24 hr in the hypothalamus of heterozygous mice, homozygous mice, and iron-deficient wild-type mice. Homozygous mice also showed higher uptake (13-15%) in some regions (hypothalamus and cerebellum) than in other regions. In wild-type and heterozygous mice, (59)Fe uptake was inversely related to brain Tf and was independent of regional brain iron concentrations and plasma Tf levels or saturation. These experimental data suggest that brain iron uptake may be constitutive and independent of plasma Tf, transferrin saturation, or regional brain iron concentration. The proteins and mechanisms responsible for additional iron uptake into specific regions, or perhaps the redistribution are unclear though the data are supportive of a non-transferrin-bound iron uptake pathway.