IRON CHAPERONE POLY C-BINDING PROTEIN 1 REGULATES IRON SENSING IN LIVERSINUSOIDAL ENDOTHELIAL CELLS

Iron is indispensable for humans, yet is toxic in excess. The mechanisms of precise iron regulation are partially understood and how systemic iron levels are sensed remains unclear. Hepcidin, secreted by hepatocytes, is the master regulator of dietary iron absorption and systemic iron balance in response to iron sufficiency. Hepatocytes are not the site of iron sensing, however. Sinusoidal endothelial cells of the liver (LSECs) sense systemic iron levels and transcriptionally activate expression of the iron-regulatory, bone morphogenetic proteins BMP6 and BMP2. Secretion of these proteins from LSECs triggers hepcidin expression in adjacent hepatocytes. The mechanisms by which LSECs sense iron are not completely known. Oxidative stress caused by iron overload can activate NRF2-mediated BMP transcription, but the activator of BMPs under conditions of physiologic iron balance remain to be identified. We hypothesize that the major iron chaperone of mammalian cells, poly C-binding protein 1 (PCBP1), plays a role in the sensing of iron in the LSECs. PCBP1 is required for binding and intracellular trafficking of chemically reactive iron in mammalian cells and tissues. Here we have constructed a LSEC-specific, mouse model of PCBP1 deletion and preliminary data indicate dysregulation of dietary iron uptake with iron deficiency and microcytic anemia. Iron deficiency was associated with inappropriately high expression of BMPs in the LSEC and high levels of hepcidin production in liver. NRF2 is not activated in the PCBP1-deleted LSECs, demonstrating PCBP1 to be a novel component in the BMP6 and hepcidin regulatory system, thereby contributing to systemic iron homeostasis.