Hypoxia signaling cascade for erythropoietin production in hepatocytes

Yutaka Tojo, Hiroki Sekine, Ikuo Hirano, Xiaoqing Pan, Tomokazu Souma, Tadayuki Tsujit, Shin Ichi Kawaguchi, Norihiko Takeda, Kotaro Takeda, Guo Hua Fong, Takashi Dan, Masakazu Ichinose, Toshio Miyata, Masayuki Yamamoto, Norio Suzuki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Erythropoietin (Epo) is produced in the kidney and liver in a hypoxia-inducible manner via the activation of hypoxia-inducible transcription factors (HIFs) to maintain oxygen homeostasis. Accelerating Epo production in hepatocytes is one plausible therapeutic strategy for treating anemia caused by kidney diseases. To elucidate the regulatory mechanisms of hepatic Epo production, we analyzed mouse lines harboring liver-specific deletions of genes encoding HIF-prolyl-hydroxylase isoforms (PHD1, PHD2, and PHD3) that mediate the inactivation of HIF1α and HIF2α under normal oxygen conditions. The loss of all PHD isoforms results in both polycythemia, which is caused by Epo overproduction, and fatty livers. We found that deleting any combination of two PHD isoforms induces polycythemia without steatosis complications, whereas the deletion of a single isoform induces no apparent phenotype. Polycythemia is prevented by the loss of either HIF2α or the hepatocyte-specific Epo gene enhancer (EpoHE). Chromatin analyses show that the histones around EpoHE dissociate from the nucleosome structure after HIF2α activation. HIF2α also induces the expression of HIF3α, which is involved in the attenuation of Epo production. These results demonstrate that the total amount of PHD activity is more important than the specific function of each isoform for hepatic Epo expression regulated by a PHD-HIF2α-EpoHE cascade in vivo.

Original languageEnglish (US)
Pages (from-to)2658-2672
Number of pages15
JournalMolecular and cellular biology
Issue number15
StatePublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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