Proposed model. Top panels: wild-type mice. Bottom panels: Tfr1 hepatocellular knockout mice. Left: low plasma iron conditions. Right: standard iron conditions. Under low iron conditions (left), plasma monoferric C and apo TF predominate. TFR1 is highly expressed. HFE is sequestered by TFR1, preventing HFE from interacting with the BMP receptor complex (BMPR-C). TFR2 is destabilized. Hamp expression is low. Under standard iron conditions (right), plasma diferric TF and monoN TF are relatively increased. TFR1 expression is low. HFE is freed from TFR1 to interact with the BMPR-C. TFR2 is stabilized and also contributes to Hamp expression. In the hepatocellular TfR1 knockout model, the absence of TFR1 prevents the sequestration of HFE as a function of diferric transferrin, resulting in excess hepcidin in both low and standard iron states. Regulation by TFR2 remains intact.