Endothelial ZIP8 plays a minor role in BMP6 regulation by iron in mice.

Iron-mediated induction of bone morphogenetic protein (BMP)6 expression by liver endothelial cells is essential for iron homeostasis regulation. We used multiple dietary and genetic mouse cohorts to demonstrate a minor functional role for the metal-ion transporter ZIP8 in regulating BMP6 expression under high-iron conditions.

BMP5 contributes to hepcidin regulation and systemic iron homeostasis in mice.

Hepcidin is the master regulator of systemic iron homeostasis. The bone morphogenetic protein (BMP) signaling pathway is a critical regulator of hepcidin expression in response to iron and erythropoietic drive. Although endothelial-derived BMP6 and BMP2 ligands have key functional roles as endogenous hepcidin regulators, both iron and erythropoietic drives still regulate hepcidin in mice lacking either or both ligands.

Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in β-thalassemia.

Transferrin receptor 1 (TfR1) performs a critical role in cellular iron uptake. Hepatocyte TfR1 is also proposed to influence systemic iron homeostasis by interacting with the hemochromatosis protein HFE to regulate hepcidin production. Here, we generated hepatocyte Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), either alone or together with Hfe knockout or β-thalassemia, to investigate the extent to which hepatocyte TfR1 function depends on HFE, whether hepatocyte TfR1 impacts hepcidin regulation by serum iron and erythropoietic signals, and its contribution to hepcidin suppression and iron overload in β-thalassemia.

Functional role of endothelial transferrin receptor 1 in iron sensing and homeostasis.

Systemic iron homeostasis is regulated by the hepatic hormone hepcidin to balance meeting iron requirements while limiting toxicity from iron excess. Iron-mediated induction of bone morphogenetic protein (BMP) 6 is a central mechanism for regulating hepcidin production. Liver endothelial cells (LECs) are the main source of endogenous BMP6, but how they sense iron to modulate BMP6 transcription and thereby hepcidin is uncertain.