Erythropoietin (EPO), a naturally occurring hormone that stimulates the production of red blood cells, is used to treat some forms of anemia. In the fetus EPO is produced by the liver. By contrast, in the adult most EPO is produced by the kidneys but some is produced by liver cells known as hepatocytes, particularly when levels of oxygen in the body are low. The role of two related proteins, HIF-1 and HIF-2 in EPO production by hepatocytes had been controversial. But now, researchers from the University of Pennsylvania, Philadelphia, have shown that in mice HIF-2 regulates hepatocyte production of EPO.
In the study, which appears in the April issue of the Journal of Clinical Investigation, Volker Haase and colleagues generated mice lacking either HIF-1-alpha or HIF-2-alpha in their hepatocytes and showed that only the mice lacking HIF-2-alpha in their hepatocytes do not produce EPO from the liver. This was observed under four different situations known to be associated with increased hepatocyte production of EPO, including early postnatal life and treatment with chemicals that mimic low levels of oxygen in the body. This identification of HIF-2 as the central regulator of EPO production by hepatocytes in mice has clinical implications for the development of therapeutics targeting the HIF-regulated pathway of EPO production for the treatment of anemia.
In an accompanying commentary, Peter Ratcliffe from the University of Oxford, United Kingdom, explains why this demonstration that different forms of HIF have distinct roles is important for developing new approaches to treat individuals with anemia.
TITLE: Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo
AUTHOR CONTACT:
Volker H. Haase
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
med.upenn
View the PDF of this article at: https://the-jci/article.php?id=30117
ACCOMPANYING COMMENTARY
TITLE: HIF-1 and HIF-2: working alone or together in hypoxia?
AUTHOR CONTACT:
Peter J. Ratcliffe
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
ox.ac
View the PDF of this article at: https://the-jci/article.php?id=31750
Contact: Karen Honey
Journal of Clinical Investigation