Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis

J Clin Invest. 2012 Dec;122(12):4635-44. doi: 10.1172/JCI63924. Epub 2012 Nov 1.

Abstract

Iron demand in bone marrow increases when erythropoiesis is stimulated by hypoxia via increased erythropoietin (EPO) synthesis in kidney and liver. Hepcidin, a small polypeptide produced by hepatocytes, plays a central role in regulating iron uptake by promoting internalization and degradation of ferroportin, the only known cellular iron exporter. Hypoxia suppresses hepcidin, thereby enhancing intestinal iron uptake and release from internal stores. While HIF, a central mediator of cellular adaptation to hypoxia, directly regulates renal and hepatic EPO synthesis under hypoxia, the molecular basis of hypoxia/HIF-mediated hepcidin suppression in the liver remains unclear. Here, we used a genetic approach to disengage HIF activation from EPO synthesis and found that HIF-mediated suppression of the hepcidin gene (Hamp1) required EPO induction. EPO induction was associated with increased erythropoietic activity and elevated serum levels of growth differentiation factor 15. When erythropoiesis was inhibited pharmacologically, Hamp1 was no longer suppressed despite profound elevations in serum EPO, indicating that EPO by itself is not directly involved in Hamp1 regulation. Taken together, we provide in vivo evidence that Hamp1 suppression by the HIF pathway occurs indirectly through stimulation of EPO-induced erythropoiesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / genetics
  • Antimicrobial Cationic Peptides / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Line, Tumor
  • Erythropoiesis*
  • Erythropoietin / physiology*
  • Gene Expression
  • Gene Expression Regulation
  • Growth Differentiation Factor 15 / blood
  • Hepatocytes / metabolism
  • Hepcidins
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Liver / cytology
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

  • Antimicrobial Cationic Peptides
  • Basic Helix-Loop-Helix Transcription Factors
  • Gdf15 protein, mouse
  • Growth Differentiation Factor 15
  • HAMP protein, human
  • Hamp protein, mouse
  • Hepcidins
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Erythropoietin
  • endothelial PAS domain-containing protein 1
  • Procollagen-Proline Dioxygenase
  • Egln1 protein, mouse
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, mouse