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Iron Homeostasis in the Liver

Erik R. Anderson, Yatrik M. Shah

10.1002/cphy.c120016

Source: Volume 3, Issue 1, January 2013

Published online: January 2013

Full Article on Wiley Online Library



Abstract

Iron is an essential nutrient that is tightly regulated. A principal function of the liver is the regulation of iron homeostasis. The liver senses changes in systemic iron requirements and can regulate iron concentrations in a robust and rapid manner. The last 10 years have led to the discovery of several regulatory mechanisms in the liver that control the production of iron regulatory genes, storage capacity, and iron mobilization. Dysregulation of these functions leads to an imbalance of iron, which is the primary cause of iron‐related disorders. Anemia and iron overload are two of the most prevalent disorders worldwide and affect over a billion people. Several mutations in liver‐derived genes have been identified, demonstrating the central role of the liver in iron homeostasis. During conditions of excess iron, the liver increases iron storage and protects other tissues, namely, the heart and pancreas from iron‐induced cellular damage. However, a chronic increase in liver iron stores results in excess reactive oxygen species production and liver injury. Excess liver iron is one of the major mechanisms leading to increased steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. © 2013 American Physiological Society. Compr Physiol 3:315‐330, 2013.

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Figure 1. Figure 1.

Systemic iron regulation. Dietary iron is absorbed through the small intestine and mainly utilized for red blood cell (RBC) production. Hepatic and splenic macrophages recycle iron from senescent RBCs. The iron derived from recycling is used for production of RBCs. During times of iron excess the liver can store iron and during increased systemic needs the liver can mobilize iron stores for utilization.
Figure 2. Figure 2.

Hepcidin regulation of ferroportin (FPN) protein expression during changes in systemic iron levels. High iron levels increase hepcidin expression, which decrease iron export from the small intestine and macrophage due to an internalization and degradation of FPN. Iron deficiency results in a decrease in hepcidin levels and stabilization of FPN protein expression.
Figure 3. Figure 3.

Regulation of hepcidin by bone morphogenetic protein (BMP)/SMAD, inflammatory and hypoxia/erythropoietic signaling in the liver. Three major pathways are critical for regulating basal and stimuli‐induced hepcidin expression. Binding of iron containing transferrin (Tf) to transferrin receptor 1 (Tfr1) causes a dissociation of Tfr1‐High Fe (HFE) complex and an interaction of HFE with Tfr2. Increased stabilization of Tfr2 increases BMP6‐mediated phosphorylation of SMAD1/5/8 and recruitment of SMAD 1/5/8 and SMAD4 to the hepcidin proximal promoter. BMP/SMAD signaling is the major pathway by which hepcidin expression is coordinated to meet systemic iron requirements. Activation of hepcidin by inflammation is thought to act independently of the BMP/SMAD pathway. The best‐studied mechanism is via the proinflammatory mediator IL‐6. Binding of IL‐6 to its receptor IL‐6 receptor (IL‐6R) initiates activation of the JAK‐STAT3 pathway. STAT3 binds directly to the proximal promoter to increase hepcidin expression. Hypoxia and erythropoiesis are inhibitors of hepcidin expression and these are the least understood pathways by which hepcidin expression is regulated. Hypoxia and erythropoiesis have been shown to inhibit hepcidin expression via direct binding of hypoxia‐inducible factor (HIF) to the proximal promoter, an erythropoietin (EPO)‐EPO receptor (EPOR)‐mediated decrease in C/EBPα expression, and through increase in an unknown erythroid derived factor which signals through an undefined pathway.
Figure 4. Figure 4.

Mechanisms of liver iron uptake. Iron is imported into the liver via Tf/Tfr‐mediated endocytosis. As the pH of the endocytic vesicle drops, iron is released, reduced to Fe2+ by an endocytic reductase, and transported out by DMT1 and/or ZIP14. During iron overload a significant amount of NTBI is present. Iron can be directly transported into the liver through membrane bound DMT1 and/or ZIP14. During conditions of increased hemolysis, the liver is capable of transport of hemoglobin and heme. Free hemoglobin binds with high affinity to haptoglobin, whereas free heme binds to hemopexin. These complexes bind to their respective receptors CD163 and Lrp/CD91, which initiate receptor‐meditated endocytosis. Hemoglobin is degraded in the endosome and heme is released from the endocytic vesicle. Heme is further degraded by HO‐1 releasing iron.
Figure 5. Figure 5.

Iron‐induced liver damage. Iron accumulation in hepatocytes and Kupffer cells leads to an increase in reactive oxygen species (ROS) production and proinflammatory mediators. Both ROS and proinflammatory mediators initiate a feed forward cycle, which activates stellate cells, initiates cell damage, and leads to loss of function contributing to an increase in steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).


Figure 1.

Systemic iron regulation. Dietary iron is absorbed through the small intestine and mainly utilized for red blood cell (RBC) production. Hepatic and splenic macrophages recycle iron from senescent RBCs. The iron derived from recycling is used for production of RBCs. During times of iron excess the liver can store iron and during increased systemic needs the liver can mobilize iron stores for utilization.



Figure 2.

Hepcidin regulation of ferroportin (FPN) protein expression during changes in systemic iron levels. High iron levels increase hepcidin expression, which decrease iron export from the small intestine and macrophage due to an internalization and degradation of FPN. Iron deficiency results in a decrease in hepcidin levels and stabilization of FPN protein expression.



Figure 3.

Regulation of hepcidin by bone morphogenetic protein (BMP)/SMAD, inflammatory and hypoxia/erythropoietic signaling in the liver. Three major pathways are critical for regulating basal and stimuli‐induced hepcidin expression. Binding of iron containing transferrin (Tf) to transferrin receptor 1 (Tfr1) causes a dissociation of Tfr1‐High Fe (HFE) complex and an interaction of HFE with Tfr2. Increased stabilization of Tfr2 increases BMP6‐mediated phosphorylation of SMAD1/5/8 and recruitment of SMAD 1/5/8 and SMAD4 to the hepcidin proximal promoter. BMP/SMAD signaling is the major pathway by which hepcidin expression is coordinated to meet systemic iron requirements. Activation of hepcidin by inflammation is thought to act independently of the BMP/SMAD pathway. The best‐studied mechanism is via the proinflammatory mediator IL‐6. Binding of IL‐6 to its receptor IL‐6 receptor (IL‐6R) initiates activation of the JAK‐STAT3 pathway. STAT3 binds directly to the proximal promoter to increase hepcidin expression. Hypoxia and erythropoiesis are inhibitors of hepcidin expression and these are the least understood pathways by which hepcidin expression is regulated. Hypoxia and erythropoiesis have been shown to inhibit hepcidin expression via direct binding of hypoxia‐inducible factor (HIF) to the proximal promoter, an erythropoietin (EPO)‐EPO receptor (EPOR)‐mediated decrease in C/EBPα expression, and through increase in an unknown erythroid derived factor which signals through an undefined pathway.



Figure 4.

Mechanisms of liver iron uptake. Iron is imported into the liver via Tf/Tfr‐mediated endocytosis. As the pH of the endocytic vesicle drops, iron is released, reduced to Fe2+ by an endocytic reductase, and transported out by DMT1 and/or ZIP14. During iron overload a significant amount of NTBI is present. Iron can be directly transported into the liver through membrane bound DMT1 and/or ZIP14. During conditions of increased hemolysis, the liver is capable of transport of hemoglobin and heme. Free hemoglobin binds with high affinity to haptoglobin, whereas free heme binds to hemopexin. These complexes bind to their respective receptors CD163 and Lrp/CD91, which initiate receptor‐meditated endocytosis. Hemoglobin is degraded in the endosome and heme is released from the endocytic vesicle. Heme is further degraded by HO‐1 releasing iron.



Figure 5.

Iron‐induced liver damage. Iron accumulation in hepatocytes and Kupffer cells leads to an increase in reactive oxygen species (ROS) production and proinflammatory mediators. Both ROS and proinflammatory mediators initiate a feed forward cycle, which activates stellate cells, initiates cell damage, and leads to loss of function contributing to an increase in steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).

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Article Title: Iron Homeostasis in the Liver
 

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Erik R. Anderson, Yatrik M. Shah. Iron Homeostasis in the Liver. Compr Physiol 2013, 3: 315-330. doi: 10.1002/cphy.c120016