Ferroportin-1 behaves as a negative acute phase protein in rat liver

Liver is the central organ of iron metabolism. During acute-phase-response (APR) serum-iron-concentration rapidly decreases. Current study aimed to compare the changes of iron-transport-protein ferroportin-1-(Fpn-1) and of other iron-import-proteins after experimental tissue damage induced by injecting turpentine-oil-(TO) in hind-limbs of rats and mice.

Serum and spleen iron-concentration decreased with an increase in total liver, cytoplasmic and nuclear iron-concentration. In liver, mRNA-amount of ferroportin-1-(Fpn-1)-, ferroportin-1-a-(Fpn-1a), ferroportin-1-b-(Fpn-1b), HFE-, hemojuvelin-(HJV)- and hephastin-(heph) genes showed a rapid decrease. Hepcidin, divalent-metal-transporter-1-(DMT-1), transferring-(Tf) and Tf-receptor-1-(TfR1), Tf-receptor-2-(TfR2) gene-expression was increased. Western-blot analysis of liver tissue lysate confirmed the changes observed at mRNA level. In spleen, a rapid decrease in gene-expression of Fpn-1, Fpn-1a, Fpn-1b, DMT-1, Tf, TfR1 and TfR2 and an increase in hepcidin was observed.

In livers of wild-type-mice, gene-expression of Fpn-1, Fpn-1a and Fpn-1b was downregulated whereas hepcidin gene-expression was increased. In contrast, these changes were less pronounced in IL-6-ko-mice.

Cytokines-(IL-6, IL-1β and TNF-α) treatment of rat-hepatocytes showed a downregulation of Fpn-1, Fpn-1a and Fpn-1b and upregulation of hepcidin gene-expression. Moreover, Western-blot analysis of cell lysate of IL-6 treated hepatocytes detected as expected an increase of α2-macroglobulin (positive acute-phase-protein) while albumin (negative acute-phase-protein) and Fpn-1 were downregulated.

Our results demonstrate that liver behaves as a „sponge” for iron under acute phase conditions and Fpn-1 behaves as a negative acute-phase-protein in rat hepatocytes mainly but not exclusively because of the effect of IL-6. These changes could explain iron retention in the cytoplasm and in the nucleus of hepatocytes during APR.