Physiologic Role of the Menkes Copper ATPase (Atp7a) in Intestinal Iron Transport

Abstract

Atp7a is a copper transporting ATPase involved in intestinal copper export that is strongly induced in the intestine of iron deficient rats. We evaluated the possible role of Atp7a in iron homeostasis in Atp7a knock down (KD) rat intestinal epithelial (IEC‐6) cells and Brindle mice that express a mutant, inactive form of Atp7a. In KD cells with >90% decrease in Atp7a protein levels, copper loading led to significantly increased intracellular Cu levels, demonstrating a reduction in the copper export function of Atp7a. Iron (59Fe) transport studies in IEC‐6 cells grown in bicameral cell culture inserts revealed significant transepithelial iron flux when cells were deprived of iron. Transport in Atp7a KD cells showed that 59Fe transported into cells and transferred to the basolateral chamber was reduced. Next, Brindled mice were rescued by perinatal copper injection and studies were done to consider the in vivo role of Atp7a in iron absorption. Brindled mice were anemic compared to wild type littermates, and Dmt1, TfR1 and Atp7a expression was induced by dietary iron deprivation. Furthermore, serum ferroxidase activity, reflecting ceruloplasmin, was decreased in Brindled mice as was activity of a novel cytosolic ferroxidase in enterocytes. These data demonstrate a physiologic role for Atp7a in intestinal iron transport possibly related to copper delivery to multi‐copper ferroxidases involved in iron homeostasis.Grant Funding Source : NIH