Liver iron sensing and body iron homeostasis

Abstract

The liver orchestrates systemic iron balance by producing and secreting hepcidin. Known as the iron hormone, hepcidin induces degradation of the iron exporter ferroportin to control iron entry into the bloodstream from dietary sources, iron recycling macrophages, and body stores. Under physiologic conditions, hepcidin production is reduced by iron deficiency and erythropoietic drive to increase the iron supply when needed to support red blood cell production and other essential functions. Conversely, hepcidin production is induced by iron loading and inflammation to prevent the toxicity of iron excess and limit its availability to pathogens. The inability to appropriately regulate hepcidin production in response to these physiologic cues underlies genetic disorders of iron overload and deficiency, including hereditary hemochromatosis and iron-refractory iron deficiency anemia. Moreover, excess hepcidin suppression in the setting of ineffective erythropoiesis contributes to iron-loading anemias such as β-thalassemia, whereas excess hepcidin induction contributes to iron-restricted erythropoiesis and anemia in chronic inflammatory diseases. These diseases have provided key insights into understanding the mechanisms by which the liver senses plasma and tissue iron levels, the iron demand of erythrocyte precursors, and the presence of potential pathogens and, importantly, how these various signals are integrated to appropriately regulate hepcidin production. This review will focus on recent insights into how the liver senses body iron levels and coordinates this with other signals to regulate hepcidin production and systemic iron homeostasis.

Figure 1.

Systemic iron homeostasis regulation by hepcidin and ferroportin. Hepcidin and ferroportin control iron entry into the circulation from dietary sources and body stores to maintain systemic iron homeostasis. Iron deficiency and erythropoietic demand suppress hepcidin production by hepatocytes (left). In the absence of hepcidin, ferroportin is stabilized on the basolateral surface of duodenal enterocytes, iron-recycling macrophages, and hepatocytes, where it transports iron (Fe) from the intracellular space to the plasma for loading onto transferrin (TF) and delivery to red blood cells and other tissues. Iron loading and inflammation stimulate hepatocyte hepcidin production and secretion into the circulation, where it binds to ferroportin to cause its ubiquitination (U), endocytosis, and degradation (right). Hepcidin binding also interferes with ferroportin export activity independent of endocytosis. Hepcidin thereby limits iron overload and sequesters iron from invading pathogens.

Figure 2.

Current model of iron sensing in the liver to regulate hepcidin production. Both tissue iron and plasma iron levels are sensed by the liver to regulate hepcidin production. Iron loading increases transferrin-bound iron (2Fe-TF) and non–transferrin-bound iron (NTBI) in the circulation (right). Iron is taken up by liver endothelial cells (ECs), which play an important role in sensing tissue iron levels. Iron loading in ECs increase BMP6 and, to a lesser extent, BMP2 expression. BMP6 is partially regulated by nuclear factor (erythroid-derived 2)-like 2 (NRF2), which is activated by iron-induced reactive oxygen species. The increased BMP2 and BMP6 bind to HJV on the hepatocyte membrane and facilitate the formation of a signaling complex consisting of BMP type I and type II receptors (BMPR1 and BMPRII). Neogenin (Neo), a scaffold protein binding to HJV, assists with the signaling complex formation and localization. The signaling complex phosphorylates SMAD1/5/8, which binds to SMAD4 and translocates to the nucleus to induce hepcidin (Hamp) transcription. Plasma iron loading is also sensed directly by hepatocytes, where 2Fe-TF binds to TFR1 and TFR2 on the hepatocyte membrane, favoring the displacement of HFE from TFR1 and the interaction between HFE and TFR2. Both HFE and TFR2 stimulate hepcidin expression via a functional interaction with the SMAD pathway, possibly by forming a complex with HJV and stabilizing BMP type I receptor ALK3. Under low-iron conditions, BMP2 and BMP6 ligand production is reduced in ECs (left). HFE binds to TFR1, whose expression levels increase, whereas TFR2 levels decrease. Iron deficiency also increases TMPRSS6/matriptase-2 (MT2) and furin, which cleave membrane HJV to generate soluble HJV (sHJV). Suppression of BMP expression, HJV cleavage from the membrane, sequestration of HFE with TFR1, and reduced TFR2 expression all diminish BMP-SMAD signaling, thus suppressing hepcidin expression.