Dietary Iron Increases Expression of Liver Hepcidin Relative to BMP6 By a Mechanism Involving Transferrin Receptor 2 and Specificity of Transferrin Lobe Iron Occupancy

Introduction: Prior studies have identified two iron signals regulating liver hepcidin expression (PMID 21488083, 21480335). One is mediated by liver sinusoidal BMP6 (and BMP2) and is reflective of liver iron concentration (LIC). The other is independent of BMP expression and reflective of transferrin saturation. The mechanism by which TF regulates hepcidin is unclear but appears to involve hepatocellular transferrin receptor 2 (TFR2). We previously generated mice with TF mutations that block iron binding to either N-lobe (Tf N-bl) or C-lobe (Tf C-bl). These mice demonstrated differences in Epo sensitivity and hepcidin regulation (PMID 31434707). To characterize the differential regulation of Hamp1 in these mice we analyzed the effect of dietary iron in juvenile mice. This model advantages a physiologic low iron state with very low basal Hamp1 and Bmp6 expression.