Is the iron donor lipocalin 2 implicated in the pathophysiology of hereditary hemochromatosis?

Under normal conditions, iron is taken up by the cells through the transferrin-mediated pathway. However, in hereditary hemochromatosis, a common iron-overloading disorder associated with mutations in the HFE gene, iron in plasma exceeds transferrin-binding capacity, and non-transferrin-bound iron (NTBI) appears in the circulation of patients with iron overload. NTBI can be taken up by hepatocytes through a transferrin-independent pathway. Lipocalin 2 (Lcn2), a secreted protein of the lipocalin family, has emerged as the mediator of an alternative, transferrin-independent pathway for cellular iron delivery. To evaluate the importance of Lcn2 in the pathogenesis of hepatic iron loading in Hfe knockout mice, we generated HfeLcn2 double-deficient mice. Our studies revealed that deletion of Lcn2 in Hfe-knockout mice does not influence hepatic iron accumulation in Hfe(-/-) mice, or their response to iron loading, as the phenotype of HfeLcn2(-/-) mice remained indistinguishable from that of Hfe(-/-) mice.

Lcn2 is not essential for iron delivery to hepatocytes in hemochromatosis.