Copper deficiency increases iron absorption in the rat

Abstract

Release of iron from enterocytes and hepatocytes is thought to require the copper-dependent ferroxidase activity of hephaestin (Hp) and ceruloplasmin (Cp), respectively. In swine, copper deficiency (CD) impairs iron absorption, but whether this occurs in rats is unclear. By feeding a diet deficient in copper, CD was produced, as evidenced by the loss of copper-dependent plasma ferroxidase I activity, and in enterocytes, CD reduced copper levels and copper-dependent oxidase activity. Hematocrit was reduced, and liver iron was doubled. CD reduced duodenal mucosal iron and ferritin, whereas CD increased iron absorption. Duodenal mucosal DMT1-IRE and ferroportin1 expression remained constant with CD. When absorption in CD rats was compared with that seen normally and in iron-deficient anemic animals, strong correlations were found among mucosal iron, ferritin, and iron absorption, suggesting that the level of iron absorption was appropriate given that the erythroid and stores stimulators of iron absorption are opposed in CD. Because CD reduced the activity of Cp, as evidenced by copper-dependent plasma ferroxidase I activity and hepatocyte iron accumulation, but iron absorption increased, it is unlikely that the ferroxidase activity of Hp is important and suggests another function for this protein in the export of iron from the enterocyte during iron absorption. Also, the copper-dependent ferroxidase activity of Cp does not appear important for iron efflux from macrophages, because Kupffer cells of the liver and nonheme iron levels of the spleen were normal during copper deficiency, suggesting another role for Cp in these cells.

Localization of iron metabolism–related mRNAs in rat liver indicate that HFE is expressed predominantly in hepatocytes

“…The finding that Kupffer cells have detectable levels of hephaestin was surprising because when hephaestin was initially cloned, little was detected in the liver by Northern analysis. 21 The link between iron export and ceruloplasmin synthesis comes from a recent report that shows that rats with lowered ceruloplasmin ferrioxidase activity as a result of a copper-poor diet had a 2-fold increase in liver iron levels 33 and from studies showing that aceruloplasminemic mice have high liver iron levels. 34 These results imply that hephaestin expression in the Kupffer cells is not sufficient to compensate for loss of ceruloplasmin.…”

Iron Imports. III. Transfer of iron from the mucosa into circulation

“…Although copper-deficient pigs show marked iron accumulation in the intestine, this phenomenon is not as pronounced in rodent models of copper deficiency. Conversely, copper deficiency in swine is associated with diminished liver iron, whereas iron accumulates in hepatocytes of copper-deficient rats (24). The latter observation suggests that intestinal iron absorption may not be as severely compromised in copper-deficient rodents, but unfortunately conflicting data indicate both decreased (21) or increased uptake (24) in copper-deficient rats.…”

“…Conversely, copper deficiency in swine is associated with diminished liver iron, whereas iron accumulates in hepatocytes of copper-deficient rats (24). The latter observation suggests that intestinal iron absorption may not be as severely compromised in copper-deficient rodents, but unfortunately conflicting data indicate both decreased (21) or increased uptake (24) in copper-deficient rats. On the basis of the latter observations, the authors suggest that hephaestin may have functions in the pathway of iron absorption that do not require its copper-dependent ferroxidase activity.…”

Mineral and vitamin deficiencies can accelerate the mitochondrial decay of aging

“…Additionally copper reverses the inactivation of ferrochelatase by lead or cobalt (Co) (Wagner and Tephly, 1975). Copper deficiency increases dietary iron absorption (Thomas and Oates, 2003) probably a compensatory mechanism to increase heme production. A rat model for WilsonÕs disease, a disorder of copper transport, exhibits abnormal heme metabolism (Nakayama et al, 2000), supporting the connection between copper and heme biosynthesis.…”