FIGURE 6 .

Effect of CuD on hepcidin regulation in rats and mice. In rats, CuD decreases Cp ferroxidase activity, which likely reduces plasma iron concentrations. Low plasma iron levels limit iron supply to the bone marrow, resulting in anemia, a suppressor of hepcidin expression. Diminished plasma iron concentrations are associated with lower levels of hepatic TfR2, a putative body iron sensor that modulates hepcidin expression according to plasma iron concentrations. Although CuD decreases Cp activity in mice, plasma iron levels are normal, possibly due to additional plasma ferroxidases. The anemia in CuD does not appear to result from limited iron supply to the bone marrow but rather to a defect in bone marrow iron utilization. Yet despite the anemia, CuD mice have normal levels of hepcidin, possibly related to normal plasma iron levels. The normal levels of hepcidin in anemic, CuD mice likely accounts for the normal Fpn levels in these animals. The question marks identify gaps in our understanding of these relationships.