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

Abstract

Iron and copper have similar physiochemical properties; thus, physiologically relevant interactions seem likely. Indeed, points of intersection between these two essential trace minerals have been recognized for many decades, but mechanistic details have been lacking. Investigations in recent years have revealed that copper may positively influence iron homeostasis, and also that iron may antagonize copper metabolism. For example, when body iron stores are low, copper is apparently redistributed to tissues important for regulating iron balance, including enterocytes of upper small bowel, the liver, and blood. Copper in enterocytes may positively influence iron transport, and hepatic copper may enhance biosynthesis of a circulating ferroxidase, ceruloplasmin, which potentiates iron release from stores. Moreover, many intestinal genes related to iron absorption are transactivated by a hypoxia-inducible transcription factor, hypoxia-inducible factor-2α (HIF2α), during iron deficiency. Interestingly, copper influences the DNA-binding activity of the HIF factors, thus further exemplifying how copper may modulate intestinal iron homeostasis. Copper may also alter the activity of the iron-regulatory hormone hepcidin. Furthermore, copper depletion has been noted in iron-loading disorders, such as hereditary hemochromatosis. Copper depletion may also be caused by high-dose iron supplementation, raising concerns particularly in pregnancy when iron supplementation is widely recommended. This review will cover the basic physiology of intestinal iron and copper absorption as well as the metabolism of these minerals in the liver. Also considered in detail will be current experimental work in this field, with a focus on molecular aspects of intestinal and hepatic iron-copper interplay and how this relates to various disease states. © 2018 American Physiological Society. Compr Physiol 8:1433-1461, 2018.

The Role of Fe, Zn, and Cu in Pregnancy

“…Some researchers suggest a separate mechanism for the absorption of heme Fe which involves heme carrier protein (HCP1), where Fe 2+ is transported through the apical membrane of the small intestine to enter the enterocytes, and then binds to apoferritin to form ferritin, a compound used to store Fe 2+ [58,59]. However, not all researchers agree that HCP1 plays this role [60]. For example, a study by Qiu et al [61] confirms the thesis that patients with a mutation in the gene encoding HCP1/PCFT have a folate deficiency, with Fe metabolism intact.…”

“…For example, a study by Qiu et al [61] confirms the thesis that patients with a mutation in the gene encoding HCP1/PCFT have a folate deficiency, with Fe metabolism intact. This shows that mechanism of heme absorption via the intestines is still undefined [60]. The surplus Fe 2+ in the enterocytes is transported to the bloodstream by ferroportin (IREG1) and reoxidized to Fe 3+ by hephaestin and ceruloplasmin, then immediately bound to the major iron-binding plasma proteinapotransferrin to form transferrin [62,63].…”

A Preliminary Study of Cu Exposure Effects upon Alzheimer’s Amyloid Pathology

“…Iron response elements typically respond to cellular iron, dissociating from the iron response proteins that bind to them and inhibit translation; thus the presence of iron enables translation [92]. The regulation of copper and iron metabolism and intake/export are linked on both systemic and cellular levels, and the excess of copper due to dietary consumption may correspondingly increase the availability of iron in the SH-SY5Y cells [93,94]. These results were confirmed in vivo, as copper fed mice exhibited increased expression of the APP gene and copper transporter ATP7B relative to the control, β-actin.…”

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Disease: Evidence from Phenome-wide Mendelian Randomization Study

“…First, the efflux of iron from enterocyte, hepatocyte, and macrophage into the blood circulation requires the action of two copper-dependent ferroxidases (i.e., hephaestin and ceruloplasmin), which oxidize ferrous iron into ferric iron so that it could be loaded onto transferrin. Besides enabling iron transport, copper is also required for hemoglobin biosynthesis, probably by assisting iron import into or utilization in mitochondria 45 .…”