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

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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.

Figure 1. Figure 1. Iron and copper metabolism in mammals, highlighting points of intersection between these two essential trace minerals. Iron and copper homeostasis during physiological conditions is displayed with points of iron‐copper intersection demarcated by yellow stars. Copper movement is indicated with green lines and iron flux in a rust color. Both minerals are absorbed in the duodenum. The inset shows points of iron‐copper intersection in a duodenal enterocyte; more details are provided in Figure 2. Copper is mainly incorporated into ceruloplasmin (CP) in hepatocytes, which is secreted into the blood where it functions predominantly in iron metabolism, facilitating iron release from some tissues. A membrane‐anchored form of CP, GPI‐CP, has a similar function in some tissues. Excess body copper is excreted in bile. Ferric iron binds transferrin (TF) in the portal blood, and after reduction and import into the liver, it is utilized for metabolic purposes or stored in hepatocytes within ferritin. Ferrous iron is then exported into the serum by FPN1, where it is oxidized by CP and then binds to TF for distribution in the blood. Most diferric‐TF is taken up by immature red blood cells in the bone marrow and utilized predominantly for hemoglobin synthesis. Iron utilization by developing erythrocytes is copper dependent, although the mechanism by which this occurs is unclear. Iron is also taken up into other tissues, including the brain, where iron release requires GPI‐CP. The FOX zyklopen, a copper‐dependent protein, may be required for proper iron flux in the placenta. Iron within hemoglobin of senescent red blood cells is recovered and stored by RE macrophages in spleen, bone marrow, and liver (i.e., Kupffer cells). Iron release from these macrophages requires CP or possibly GPI‐CP. Iron homeostasis is regulated by hepcidin, which modulates iron flux by inhibiting intestinal iron absorption and iron release from stores in RE macrophages and hepatocytes. Hepcidin may be stabilized by copper, exemplifying another point of iron‐copper intersection. Iron is lost from the body predominantly by desquamation of skin cells and exfoliation of enterocytes, and by blood loss, since no active, regulatory excretory system for iron has evolved in humans.
Figure 2. Figure 2. Iron‐copper metabolism in a duodenal enterocyte, highlighting points of intersection between these two essential trace minerals. A duodenal enterocyte is depicted along with the proteins which mediate iron and copper absorption. Points where iron and copper metabolism intersect are demarcated by yellow stars. Both metals require reduction prior to absorption, which may be mediated by DCYTB and/or other reductases. Subsequently, iron is transported along with protons across the BBM by DMT1. The electrochemical proton gradient across the BBM that provides the driving force for ferrous iron transport is maintained via the action of a sodium‐hydrogen antiporter (NHE3) and the Na+/K+ ATPase on the BLM. DMT1 may also transport copper during iron deficiency (FeD). High‐iron (HFe) intake may block copper transport by DMT1 and/or CTR1, eventually leading to copper depletion. Cytosolic iron may be transported into mitochondria for metabolic use, stored in ferritin, or exported across the BLM by FPN1. FPN1 activity may be impacted by copper. Ferrous iron must then be oxidized by HEPH, CP, or other FOXs (not shown) to enable binding to TF in the interstitial fluids. After reduction, dietary copper is transported into enterocytes by CTR1 and is then distributed to various cellular locations by intracellular copper‐binding proteins (i.e. chaperones). Excess copper may be stored in the cell by MT. Copper is pumped into the TGN by ATP7A, supporting cuproenzyme synthesis, or exported from the cell by ATP7A, which moves to the BLM when copper is in excess. ATP7A expression is strongly upregulated by iron depletion, suggesting that it (or copper) may positively influence iron metabolism in enterocytes. Copper is spontaneously oxidized by dissolved oxygen in the blood and then bound to mainly albumin and α2‐macrogloubuoin in the portal blood and delivered to the liver.
Figure 3. Figure 3. Iron‐copper metabolism in a hepatocyte, highlighting points of intersection between these two essential trace minerals. Iron‐copper interactions within hepatocytes are indicated by yellow stars. Hepatocytes produce and secrete the iron‐regulatory, peptide hormone hepcidin (not shown), which alters intestinal iron absorption (thus justifying the consideration of liver iron homeostasis in this review). Hepcidin also acts in an autocrine fashion to block iron release from hepatocytes (bottom left). Copper may stabilize hepcidin, and thus influence its activity. Hepatocytes also play a principal role in copper metabolism by mediating the excretion of excess copper in bile. These cells assimilate iron via receptor‐mediated endocytosis of diferric‐TF via transferrin receptors (TFR1/2). Iron is subsequently released from TF by the action of an H+‐ATPase in endosomes, reduced (perhaps by STEAP3), and is then transported into the cytosol by DMT1 (or ZIP14). Under pathological conditions of iron overload, nontransferrin bound (ferric) iron in the blood may be reduced and taken up into hepatocytes by ZIP14. This reductase may also reduce copper. Iron is used in cells for metabolic purposes, stored in ferritin, or exported by FPN1 (which may be influenced by copper levels). After reduction, cuprous copper is taken up into hepatocytes via CTR1 and distributed by chaperones. ATOX1 delivers copper to ATP7B, which transports copper into the TGN for incorporation into cuproenzymes, including the FOXs CP and GPI‐CP. These FOXs mediate the oxidation of ferrous iron (in an autocrine manner) after release by hepatocytes or other cells (by paracrine of endocrine actions) to permit ferric iron binding to TF in the interstitial fluids. ATP7B also transports excess copper across the canalicular membrane into bile for excretion. ATP7B activity is modulated by COMMD1, and XIAP, a ubiquitin ligase which mediates proteasomal degradation of COMMD1.


Figure 1. Iron and copper metabolism in mammals, highlighting points of intersection between these two essential trace minerals. Iron and copper homeostasis during physiological conditions is displayed with points of iron‐copper intersection demarcated by yellow stars. Copper movement is indicated with green lines and iron flux in a rust color. Both minerals are absorbed in the duodenum. The inset shows points of iron‐copper intersection in a duodenal enterocyte; more details are provided in Figure 2. Copper is mainly incorporated into ceruloplasmin (CP) in hepatocytes, which is secreted into the blood where it functions predominantly in iron metabolism, facilitating iron release from some tissues. A membrane‐anchored form of CP, GPI‐CP, has a similar function in some tissues. Excess body copper is excreted in bile. Ferric iron binds transferrin (TF) in the portal blood, and after reduction and import into the liver, it is utilized for metabolic purposes or stored in hepatocytes within ferritin. Ferrous iron is then exported into the serum by FPN1, where it is oxidized by CP and then binds to TF for distribution in the blood. Most diferric‐TF is taken up by immature red blood cells in the bone marrow and utilized predominantly for hemoglobin synthesis. Iron utilization by developing erythrocytes is copper dependent, although the mechanism by which this occurs is unclear. Iron is also taken up into other tissues, including the brain, where iron release requires GPI‐CP. The FOX zyklopen, a copper‐dependent protein, may be required for proper iron flux in the placenta. Iron within hemoglobin of senescent red blood cells is recovered and stored by RE macrophages in spleen, bone marrow, and liver (i.e., Kupffer cells). Iron release from these macrophages requires CP or possibly GPI‐CP. Iron homeostasis is regulated by hepcidin, which modulates iron flux by inhibiting intestinal iron absorption and iron release from stores in RE macrophages and hepatocytes. Hepcidin may be stabilized by copper, exemplifying another point of iron‐copper intersection. Iron is lost from the body predominantly by desquamation of skin cells and exfoliation of enterocytes, and by blood loss, since no active, regulatory excretory system for iron has evolved in humans.


Figure 2. Iron‐copper metabolism in a duodenal enterocyte, highlighting points of intersection between these two essential trace minerals. A duodenal enterocyte is depicted along with the proteins which mediate iron and copper absorption. Points where iron and copper metabolism intersect are demarcated by yellow stars. Both metals require reduction prior to absorption, which may be mediated by DCYTB and/or other reductases. Subsequently, iron is transported along with protons across the BBM by DMT1. The electrochemical proton gradient across the BBM that provides the driving force for ferrous iron transport is maintained via the action of a sodium‐hydrogen antiporter (NHE3) and the Na+/K+ ATPase on the BLM. DMT1 may also transport copper during iron deficiency (FeD). High‐iron (HFe) intake may block copper transport by DMT1 and/or CTR1, eventually leading to copper depletion. Cytosolic iron may be transported into mitochondria for metabolic use, stored in ferritin, or exported across the BLM by FPN1. FPN1 activity may be impacted by copper. Ferrous iron must then be oxidized by HEPH, CP, or other FOXs (not shown) to enable binding to TF in the interstitial fluids. After reduction, dietary copper is transported into enterocytes by CTR1 and is then distributed to various cellular locations by intracellular copper‐binding proteins (i.e. chaperones). Excess copper may be stored in the cell by MT. Copper is pumped into the TGN by ATP7A, supporting cuproenzyme synthesis, or exported from the cell by ATP7A, which moves to the BLM when copper is in excess. ATP7A expression is strongly upregulated by iron depletion, suggesting that it (or copper) may positively influence iron metabolism in enterocytes. Copper is spontaneously oxidized by dissolved oxygen in the blood and then bound to mainly albumin and α2‐macrogloubuoin in the portal blood and delivered to the liver.


Figure 3. Iron‐copper metabolism in a hepatocyte, highlighting points of intersection between these two essential trace minerals. Iron‐copper interactions within hepatocytes are indicated by yellow stars. Hepatocytes produce and secrete the iron‐regulatory, peptide hormone hepcidin (not shown), which alters intestinal iron absorption (thus justifying the consideration of liver iron homeostasis in this review). Hepcidin also acts in an autocrine fashion to block iron release from hepatocytes (bottom left). Copper may stabilize hepcidin, and thus influence its activity. Hepatocytes also play a principal role in copper metabolism by mediating the excretion of excess copper in bile. These cells assimilate iron via receptor‐mediated endocytosis of diferric‐TF via transferrin receptors (TFR1/2). Iron is subsequently released from TF by the action of an H+‐ATPase in endosomes, reduced (perhaps by STEAP3), and is then transported into the cytosol by DMT1 (or ZIP14). Under pathological conditions of iron overload, nontransferrin bound (ferric) iron in the blood may be reduced and taken up into hepatocytes by ZIP14. This reductase may also reduce copper. Iron is used in cells for metabolic purposes, stored in ferritin, or exported by FPN1 (which may be influenced by copper levels). After reduction, cuprous copper is taken up into hepatocytes via CTR1 and distributed by chaperones. ATOX1 delivers copper to ATP7B, which transports copper into the TGN for incorporation into cuproenzymes, including the FOXs CP and GPI‐CP. These FOXs mediate the oxidation of ferrous iron (in an autocrine manner) after release by hepatocytes or other cells (by paracrine of endocrine actions) to permit ferric iron binding to TF in the interstitial fluids. ATP7B also transports excess copper across the canalicular membrane into bile for excretion. ATP7B activity is modulated by COMMD1, and XIAP, a ubiquitin ligase which mediates proteasomal degradation of COMMD1.
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Teaching Material

C. Doguer, J. -H. Ha, J. F. Collins. Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver. Compr Physiol 8: 2018, 1433-1461

Didactic Synopsis

Major Teaching Points:

  • Iron and copper are essential nutrients for humans since they mediate numerous important physiologic functions; deficiency of either is associated with significant pathophysiologic outcomes.
  • Iron and copper exist in two oxidation states in biological systems, and high redox potentials lead to toxicity in cells and tissues when in excess.
  • Iron and copper atoms have similar physiochemical properties, and as such, interactions between them are predictable.
  • Both minerals are absorbed by duodenal enterocytes, after first being reduced in the gut lumen from their predominant dietary forms.
  • Two multicopper ferroxidases perhaps best exemplify iron-copper interactions: hephaestin (HEPH) in duodenal enterocytes and ceruloplasmin (CP) circulating in the plasma. HEPH is required for optimal intestinal iron absorption during physiologic conditions and during pregnancy, while CP is required for iron release from stores and other tissues (e.g., brain) (CP).
  • Intestinal and hepatic ferrireductases, such as duodenal cytochrome B or STEAP proteins, may promote iron and copper reduction, which is required for absorption into enterocytes and subsequent uptake into hepatocytes.
  • During iron deficiency, copper transport by into duodenal enterocytes increases, possibly promoting iron absorption. This may be mediated by the principal intestinal iron transporter, divalent metal-ion transporter 1 (DMT1), which can also transport copper.
  • Hepatic copper accumulation during iron deficiency may enhance biosynthesis of CP.
  • Intestinal genes encoding iron transporters are regulated by a hypoxia-inducible transcription factor, HIF2α. Copper enhances the DNA-binding activity of the HIFs, exemplifying another way in which copper may influence iron homeostasis.
  • Iron overload, as seen in the genetic disease hereditary hemochromatosis, may impair copper utilization. Moreover, high-dose iron supplementation may increase risk for copper depletion in humans, and as such, it has been suggested that iron supplements should also contain copper.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching. 3

Figure 1 Teaching points. This figure depicts whole-body iron and copper homeostasis. Yellow stars indicate points where iron and copper metabolism intersect. Iron and copper are absorbed in the upper small intestine (some details are depicted in the inset; more detail is provided in Figure 2), and then transported via the hepatic portal vein to the liver. Absorption of both minerals is regulated according to body requirements. The minerals can be utilized or stored in the liver, or exported into the systemic blood supply for distribution to body cells. Iron is distributed as diferric-TF, while copper binds to albumin or other serum proteins in the blood. Most iron travels to the bone marrow where it is taken up by developing erythrocytes to support hemoglobin synthesis. Senescent (i.e., dying) red blood cells are phagocytozed by RE macrophages, and the iron is liberated from the heme moiety and stored. This iron in RE macrophages can be released with iron demand increases. Iron levels in the serum are controlled by the liver-derived, iron-regulatory protein, hepcidin, which blocks intestinal iron transport and iron release from stores (in RE macrophages and hepatocytes). Hepcidin expression is regulated by proteins that sense body iron levels, and respond to changes in demand for red blood cell production and infection and inflammation. Most serum copper is incorporated into CP, which is secreted from the liver. CP, which is a copper-dependent protein, mediates iron release from some tissues by oxidizing ferrous iron to enable binding to TF. Copper also exits the liver as cuprous copper, which is spontaneously oxidized and then bound to plasma proteins. This copper is distributed to cells and tissues to meet demands for copper. Copper homeostasis is regulated by intestinal absorption and biliary excretion, but details of how this may occur are currently lacking.

Figure 2 Teaching points. This figure depicts a single duodenal enterocyte. Proteins involved in iron and copper absorption are shown. Yellow stars indicate points where iron and copper metabolism intersect. Both minerals must be reduced prior to transport into cells, possibly being mediated by the same protein (DCYTB). Iron enters cells via DMT1, while copper goes in through CTR1 (possibly by endocytosis). Supplemental iron [of high-iron (HFe) intake] may block copper absorption by DMT1 and/or CTR1. The minerals can be stored in these cells, used for metabolic purposes, or transported out to enter the portal blood circulation. Both minerals are oxidized prior to traveling to the liver as diferric-TF (iron) or bound to albumin (copper). Since free iron and copper atoms are highly reactive, they are almost always bound to proteins or other molecules, which mitigates their reactivity. Copper moves within cells bound to chaperones. The same may be true for iron, but the identity of possible iron chaperones have not been revealed to date.

Figure 3 Teaching points. This figure depicts a single hepatocyte. This cell type plays important roles in the overall homeostasis of both minerals. Proteins involved in iron and copper absorption are shown. Yellow stars indicate points where iron and copper metabolism intersect. Hepatocytes synthesizes the iron-regulatory hepcidin (not shown), which can work in an autocrine fashion to block iron release from these cells (lower left). Copper must be reduced prior to transport into cells, possibly being mediated by a protein that can also reduce iron (and allow transport into the cell by ZIP14, which likely only occurs during pathological iron overload). Iron is assimilated by hepatocytes via the TF cycle (i.e., receptor-mediated endocytosis). Copper enters via CTR1, and is parsed via intracellular copper chaperones. Iron chaperones may also exist (not shown). Iron and copper can be utilized for metabolic purposes, stored, or exported out of the cell. Both minerals are reduced upon release and then distributed in the bloodstream. Excess copper may be excreted in the liver via the action of the ATP7B copper transporter in hepatocytes.

 


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Caglar Doguer, Jung‐Heun Ha, James F. Collins. Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver. Compr Physiol 2018, 8: 1433-1461. doi: 10.1002/cphy.c170045