title: Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes.
abstract: 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.
authors.affiliation: Division of Interdisciplinary Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tojo
authors.affiliation: Division of Interdisciplinary Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sekine
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Hirano
authors.affiliation: Division of Interdisciplinary Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Souma
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan Division of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Tsujita
authors.affiliation: Division of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Kawaguchi
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takeda
authors.affiliation: Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, USA.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, USA.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Fong
authors.affiliation: Division of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Dan
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ichinose
authors.affiliation: Division of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Division of Interdisciplinary Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan sunorio@med.tohoku.ac.jp.
authors.forename: Norio
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D000740:Anemia / Q000209:etiology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004921:Erythropoietin / Q000096:biosynthesis*; D005234:Fatty Liver / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011086:Polycythemia / Q000235:genetics; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics*; D012097:Repressor Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D011393:Procollagen-Proline Dioxygenase; D012097:Repressor Proteins; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C444643:Hif3a protein, mouse; C522721:PHD1 protein, mouse; C522722:PHD3 protein, mouse; C490189:Egln1 protein, mouse