| First Author | Schwartz AJ | Year | 2019 |
| Journal | J Clin Invest | Volume | 129 |
| Issue | 1 | Pages | 336-348 |
| PubMed ID | 30352047 | Mgi Jnum | J:271235 |
| Mgi Id | MGI:6279495 | Doi | 10.1172/JCI122359 |
| Citation | Schwartz AJ, et al. (2019) Hepatic hepcidin/intestinal HIF-2alpha axis maintains iron absorption during iron deficiency and overload. J Clin Invest 129(1):336-348 |
| abstractText | Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin, a liver-derived hormone that controls iron mobilization through its molecular target ferroportin (FPN), the only known mammalian iron exporter. This pathway is perturbed in diseases that cause iron overload. Additionally, intestinal HIF-2alpha is essential for the local absorptive response to systemic iron deficiency and iron overload. Our data demonstrate a hetero-tissue crosstalk mechanism, whereby hepatic hepcidin regulated intestinal HIF-2alpha in iron deficiency, anemia, and iron overload. We show that FPN controlled cell-autonomous iron efflux to stabilize and activate HIF-2alpha by regulating the activity of iron-dependent intestinal prolyl hydroxylase domain enzymes. Pharmacological blockade of HIF-2alpha using a clinically relevant and highly specific inhibitor successfully treated iron overload in a mouse model. These findings demonstrate a molecular link between hepatic hepcidin and intestinal HIF-2alpha that controls physiological iron uptake and drives iron hyperabsorption during iron overload. |
