Intestinal divalent metal‐ion transporter‐1 is critical for intestinal iron absorption but not that of copper (996.3)

Abstract

Divalent metal‐ion transporter‐1 (DMT1) is a widely expressed iron transporter serving iron absorption and erythroid iron uptake. DMT1 can also transport certain other transition metal ions; however, questions have arisen as to the role that DMT1 plays in the absorption of copper. We tested the hypothesis that intestinal DMT1 is essential for the absorption of Fe and Cu by examining (1) hematological variables and Fe status, (2) expression of Fe‐related genes (by using RT‐qPCR), and (3) radiotracer metal absorption in a mouse model lacking intestinal DMT1 (i.e. DMT1int/int, generated by crossing floxed DMT1 and villin‐Cre transgenic lines). The DMT1int/int mouse (at age ≍ 120 d) exhibited a profound hypochromic–microcytic anemia (hemoglobin concentration was 1.8 ± SD 0.5 g/dL in DMT1int/int mice cf. 14.6 ± 0.7 g/dL in wildtype, n = 7–9), and severely depleted serum Fe and liver nonheme Fe stores. mRNA expression of Cybrd1 (ferrireductase) was increased to (30 ± 3)‐fold (mean ± propagated SE, n = 3) in enterocytes of DMT1int/int mice cf. wildtype mice and that of the basolateral Fe exporter ferroportin, (2.7 ± 1.0)‐fold. Liver Hamp1 (hepcidin) expression was depressed by 97% ± 48%. Expression of the apical Cu transporter Ctr1 was increased to (2 ± 1)‐fold in enterocytes of DMT1int/int cf. wildtype mice, consistent with other models of iron deficiency. Parenteral Fe injection corrected the hematological and serum‐Fe variables, Fe stores, and gene expression levels in the DMT1int/int mouse. We measured the absorption of 59Fe and 64Cu in mice fed by intragastric gavage. Loss of intestinal DMT1 decreased the 0–4‐hour appearance of 59Fe in blood by 88% ± 24% cf. wildtype. Enterocyte 59Fe content at 4 h was 93% ± 42% lower in DMT1int/int cf. wildtype mice, indicating that the defect was at the level of apical uptake. Intestinal handling of 64Cu in the DMT1int/int mouse was no different from wildtype (P = 0.26). We conclude that DMT1 is critical for intestinal absorption of Fe but not Cu.Grant Funding Source: Supported by PHS Grant DK080047