Submitted to: Meeting Abstract
Publication Type: Abstract only
Publication Acceptance Date: 3/10/2005
Publication Date: 7/3/2005
Citation: Reeves, P.G. 2005. Iron absorption and intestinal hephaestin protein in copper-deficient rats [abstract]. Presented at Gordon Research Conference on Cell Biology of Metals. Bates College, Lewiston, ME. July 3-8, 2005. Interpretive Summary:
Technical Abstract: More than 100 years ago, a connection between copper (Cu) and iron (Fe) metabolism was established when some forms of anemia were found to respond to treatment with Cu but not Fe. It was later discovered that the Cu-dependent plasma ferroxidase, ceruloplasmin, was associated with Fe homeostasis. Cu deficiency in animals reduced Cp activity to almost non-detectable amounts, and was associated with low plasma Fe and anemia. In the 1950s, Cartwright and colleagues performed a series of experiments in pigs and rats, which suggested that Cu deficiency reduced Fe absorption. However, in the ensuing years, inconsistencies in results of various investigators cast doubt on the involvement of Cu in Fe absorption. However, recent results from our laboratory (Reeves & DeMars, J.Nutr., 134: 1953, 2004) gave strong evidence that Cu deficiency in the rat does indeed reduce Fe absorption. In 1967, Bannerman described an X-linked hypochromic anemic (sla) condition in mice that could be cured by Fe injections, but not by supplemental dietary Fe. Vulpe and others went on to discover that this genetic anomaly was caused by the disruption of a gene that produces a multi-Cu ferroxidase (Hephaestin; Hp) located primarily in the intestinal enterocytes. This suggests that Fe2+ has to be converted to Fe3+ during export from the cell into the plasma. If this ferroxidase is affected as negatively by Cu deficiency as is ceruloplasmin, then perhaps this is the mechanism for the reduction of Fe absorption in Cu deficiency. Further studies in our laboratory (Reeves et al., J.Nutr., 135: 92, 2005) demonstrated by Western blot analysis that the relative abundance of Hp protein in the enterocytes of Cu-deficient rats was less than 50% of that in Cu-adequate rats, which correlated with reduced Fe absorption, increased mucosal Fe, decreased plasma Fe, and anemia in Cu-deficiency. Further studies showed that all these parameters, including Hp protein, could be reversed by supplementing Cu in the diets of Cu-deficient rats (Exp.Biol.Med., 230: In press, 2005). In a more recent study (not published), we gave Cu-deficient and control rats three times the normal amount of dietary Fe (35 vs. 105 mg/kg) or daily IP injections of Fe equal to that estimated to be absorbed from the high-Fe diet. After two weeks of supplementation, neither high dietary Fe nor Fe injections reversed the anemia of Cu deficiency. Furthermore, Cu deficiency reduced dietary Fe retention in both Fe supplemented groups. Thus, these studies support our previous findings that Cu deficiency reduces Fe absorption in the rat, and suggest that the reduction in enterocyte Hp protein is part of the mechanism for this effect. In addition, because Fe injections did not reverse the anemia of Cu deficiency, Cu also is involved in the delivery of Fe to the hematopoietic system for heme synthesis and/or erythropoiesis.