The liver: conductor of systemic iron balance

Abstract

Iron is a micronutrient essential for almost all organisms: bacteria, plants, and animals. It is a metal that exists in multiple redox states, including the divalent ferrous (Fe(2+)) and the trivalent ferric (Fe(3+)) species. The multiple oxidation states of iron make it excellent for electron transfer, allowing iron to be selected during evolution as a cofactor for many proteins involved in central cellular processes including oxygen transport, mitochondrial respiration, and DNA synthesis. However, the redox cycling of ferrous and ferric iron in the presence of H2O2, which is physiologically present in the cells, also leads to the production of free radicals (Fenton reaction) that can attack and damage lipids, proteins, DNA, and other cellular components. To meet the physiological needs of the body, but to prevent cellular damage by iron, the amount of iron in the body must be tightly regulated. Here we review how the liver is the central conductor of systemic iron balance and show that this central role is related to the secretion of a peptide hormone hepcidin by hepatocytes. We then review how the liver receives and integrates the many signals that report the body's iron needs to orchestrate hepcidin production and maintain systemic iron homeostasis.

Figure 1

The liver is the major source of hepcidin production. Iron and inflammation stimulate, whereas erythropoiesis, hormones, and growth factors decrease, hepcidin production. Hepcidin downregulates ferroportin in macrophages, enterocytes, and hepatocytes, leading to decreased iron release into the serum that is subsequently bound to transferrin (Fe³⁺-Tf).

Figure 2

The liver responds to iron signals to regulate hepcidin production. Hepatic iron accumulation leads to increased BMP6 production, which is an important ligand for the HJV/BMP receptor complex on the surface of hepatocytes. The activation of the BMP signaling pathway leads to nuclear translocation of SMAD1/5/8 with SMAD4 and subsequent activation of hepcidin transcription. Circulating iron–bound transferrin (Fe³⁺-Tf) also stimulates hepcidin production by activating the BMP/HJV/SMAD signaling pathway. However, the exact details of the necessary and sufficient interactions of iron-bound transferrin with transferrin receptor 1 (TFR1), transferrin receptor 2 (TFR2), and HFE at the surface of hepatocytes to stimulate hepcidin expression are still unknown. Other modulators such as matriptase-2 are important for regulating iron-induced signals that affect hepcidin production.

Figure 3

The liver responds to inflammatory signals to regulate hepcidin production. Inflammatory signals such as IL-6 and Activin B stimulate the production of hepcidin by the liver. IL-6 increases phospho-STAT3 levels and subsequently stimulates transcription of hepcidin. Activin B may stimulate the BMP receptor complex directly. Matriptase-2 may also regulate inflammatory stimulation of hepcidin. Importantly, the proximal BMP-responsive element in the hepcidin promoter is necessary for the full effect of STAT-3 stimulation on hepcidin transcription.