Hepatocytes are the major storage site for iron and also expresses a complex range of molecules which are involved in iron transport and regulation of iron homeostasis.
Iron is transported around the plasma bound mainly to the glycoprotein Transferrin. (Transferrin cycle)
In normal human plasma, transferrin has a concentration of between 25 and 50 μmol/L , and is usually about one-third saturated with iron.
The remaining, unoccupied, binding sites on transferrin provide a large buffering capacity in case of an acute increase in plasma iron levels, an important consideration given the toxicity of free iron.
Following uptake by the tissues, iron is transferred into a cytosolic pool (the transit pool ) from where it is distributed to ferritin for storage or to iron-requiring moieties, such as haem or iron-sulphur clusters.
The majority of hepatocellular iron is contained in ferritin (80%) with 2%-3% present as haem; the remainder is either bound to transferrin or present in the transit pool.
Histologically, iron is distributed around the periportal regions of the liver with a decreasing gradient towards the centrilobular regions.
Hepatocyte iron transport - (Iron input)
Hepatocyte iron uptake:
- Transferrin-bound iron uptake - TBI
- Non-transferrin iron uptake - NTBI
- Transport of other iron complexes
Fig 1 Hepatocyte iron transport. (1) TFR1-mediated uptake of diferric transferrin . Diferric transferrin binds to its specific receptor and is endocytosed. The endosome is acidified and Fe3+ is reduced by STEAP3 . The iron is released and transported out of the endosome via DMT1 and apotransferrin is exocytosed. (2) TFR2-mediated uptake of transferrin . This mechanism is similar to the TFR1-specific mechanism except that transferrin binds to TFR2. (3) Uptake of NTBI . Iron is reduced and is transported into the cell via a carrier-mediated process. (4) Uptake of ferritin . Ferritin binds to its specific receptor and is endocytosed. The endosome is directed to lysosomes and the iron is transferred to the transit pool or endogenous ferritin. (5) Uptake of haem-haemopexin . The haem-haemopexin complex binds to its specific receptor CD91 and is endocytosed. Haem is removed and is degraded by haem oxygenase. (6) Uptake of haemoglobin-haptoglobin . The haemoglobin-haptoglobin complex binds to a specific receptor. Following endocytosis, the complex may be directed to the canalicular membrane for release into the bile or to the lysosomes for degradation. (7) Uptake of lactoferrin . Lactoferrin binds to LRP or RHL-1 and is endocytosed and targeted to the lysosomes for degradation. (8) . Iron is released by FPN and oxidised by caeruloplasmin and binds to apotransferrin .
TFR1 transferrin receptor 1; TFR2 transferrin receptor 2; STEAP3 six-transmembrane epithelial antigen of the prostate 3; DMT1 divalent metal transporter 1; NTBI non-transferrin bound iron; ZIP14 zinc-regulated transporter and iron-regulated transporter-like protein 14; LRP low-density lipoprotein receptor-related protein; FPN ferroportin.
- High affinity transferrin uptake:
- Low affinity transferrin uptake:
- DMT1 and ZIP14: DMT1 and ZIP14 are probably the major transporters of NTBI in hepatocytes.
- Calcium channels: The role of calcium channels in uptake of NTBI by the liver remains unclear.
- Ferritin: Hepatocytes clear ferritin by a method involving binding to a specific ferritin receptor followed by endocytosis. There are several possible fates for endocytosed ferritin including catabolism of the protein in lysosomes, excretion in the bile or inclusion in the endogenous ferritin pool. Any iron released is distributed to the mitochondria and endogenous ferritin.
- Haemoglobin-haptoglobin complex
- Lactoferrin: Lactoferrin is an iron-binding protein similar to transferrin which is present mainly in milk.
Two lactoferrin binding sites have been reported on hepatocytes, although neither is specific for lactoferrin. The first is low-density lipoprotein receptor-related protein (LRP) and the second is the major ( RHL-1 ) subunit of the asialoglycoprotein receptor. Lactoferrin appears to be cleared via receptor-mediated endocytosis regardless of its binding site. Most of the internalised lactoferrin is directed to lysosomes for degradation.