Suppressed hepcidin expression correlates with hypotransferrinemia in copper-deficient rat pups but not dams

Abstract

Copper deficiency leads to anemia but the mechanism is unknown. Copper deficiency also leads to hypoferremia, which may limit erythropoiesis. The hypoferremia may be due to limited function of multicopper oxidases (MCO) hephaestin in enterocytes or GPIceruloplasmin in macrophages of liver and spleen whose function as a ferroxidase is thought essential for iron transfer out of cells. Iron release may also be limited by ferroportin (Fpn), the iron efflux transporter. Fpn may be lower following copper deficiency because of impaired ferroxidase activity of MCO. Fpn is also dependent on the liver hormone hepcidin as Fpn is degraded when hepcidin binds to Fpn. Anemia and hypoferremia both down regulate hepcidin by separate mechanisms. Current studies confirmed and extended earlier studies with copper-deficient (CuD) rats that suggested low hepicidin resulted in augmented Fpn. However, current studies in CuD dams failed to confirm a correlation that hepcidin expression was associated with low transferrin receptor 2 (TfR2) levels and also challenged the dogma that holotransferrin can explain the correlation with hepcidin. CuD dams exhibited hypoferremia, low liver TfR2, anemia in some rats, yet no depression in Hamp expression, the hepcidin gene. Normal levels of GDF-15, the putative erythroid cytokine that suppresses hepcidin, were detected in plasma of CuD and iron-deficient (FeD) dams. Importantly, FeD dams did display greatly lower Hamp expression. Normal hepcidin in these CuD dams is puzzling since these rats may need extra iron to meet needs of lactation and the impaired iron transfer noted previously.

Copper chelation and interleukin-6 proinflammatory cytokine effects on expression of different proteins involved in iron metabolism in HepG2 cell line

“…These results are consistent with published studies in which copper deficiency led to a decrement in TfR1 protein in the liver [73, 89]. …”

“…Different experimental models have reported some contrasting results such as animals fed a copper-deficient diet showed an increment of Fpn1 protein when whole liver was analysed. This apparent discrepancy could be due to a different response to the same stimuli between the different cells present in this organ, e.g., Kupffer cells and hepatocytes [14, 72, 73]. …”

Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver

“…For example, one recent study showed that copper treatment induced hepcidin expression in hepatoma cells via transactivation of the Hamp gene promoter by the metal-responsive transcription factor MTF1 (13). In addition, hepcidin expression is diminished in rats (27, 138) and mice (42) in response to copper depletion. Moreover, the biologically active from of the hepcidin peptide (hepcidin-25), binds copper with high affinity (292).…”

Molecular Mediators Governing Iron-Copper Interactions

“…Recent evidence shows that hepcidin expression is decreased by copper restriction in rats (4, 48) and mice (9). Furthermore, it was shown that hepcidin-25, the active form of the peptide, binds copper with high affinity (109).…”