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Deficiency of the oxygen sensor PHD1 augments liver regeneration after partial hepatectomy

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Abstract

Purpose

Liver regeneration after partial hepatectomy (PH) occurs in conditions of reduced oxygen supply. HIF prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3) are oxygen sensors involved in adaptive response to hypoxia. Specific functions of these PHD enzymes in liver regeneration have, however, remained enigmatic. Here, we investigated the significance of PHD1 in liver regeneration following hepatectomy.

Methods

Liver regeneration was studied in PHD1-deficient (PHD1−/−) and wild type (WT) mice subjected to 80 % hepatectomy. For in vitro analyses, hepatocytes were isolated from PHD1−/− and WT livers. Cell cycle progression was studied via FACS-based analysis of nuclear DNA profile. Transcription factor binding assays, qRT-PCR, and immunoblotting were applied to study the relevance of PHD1 downstream effectors during liver regeneration.

Results

Liver regeneration was significantly enhanced in PHD1−/− mice compared to WT littermates. This effect was due to enhanced proliferation rather than to hypertrophy of liver cells. Cell cycle progression was significantly enhanced, and transcriptional activity of the cell cycle regulator c-Myc was increased in PHD1-deficient hepatocytes. These changes coincided with increased expression of cyclin D2, a cell cycle-promoting c-Myc target, and decreased expression of the cell cycle-delaying c-Myc target p21.

Conclusions

Loss of PHD1 enhances liver regeneration by boosting hepatocyte proliferation in a c-Myc-dependent fashion. PHD1 might, therefore, represent a potential target to facilitate liver regeneration after surgical resection.

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Acknowledgments

This study was supported by the Emmy Noether Program of the Deutsche Forschungsgemeinschaft (DFG; Grant 947/2-1 to M.S.) and in the framework of the Clinical Research Group KFO 227 by the DFG (Grant 947/4-1 to M.S.).

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

    Martin Mollenhauer, Judit Kiss, Johanna Dudda, Johanna Kirchberg, Nuh Rahbari, Praveen Radhakrishnan, Thomas Niemietz, Vanessa Rausch, Jürgen Weitz & Martin Schneider

Authors
  1. Martin Mollenhauer
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  2. Judit Kiss
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  3. Johanna Dudda
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  4. Johanna Kirchberg
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  6. Praveen Radhakrishnan
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  7. Thomas Niemietz
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  8. Vanessa Rausch
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  9. Jürgen Weitz
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  10. Martin Schneider
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Corresponding author

Correspondence to Martin Schneider.

Additional information

Martin Mollenhauer and Judit Kiss contributed equally to this work.

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Mollenhauer, M., Kiss, J., Dudda, J. et al. Deficiency of the oxygen sensor PHD1 augments liver regeneration after partial hepatectomy. Langenbecks Arch Surg 397, 1313–1322 (2012). https://doi.org/10.1007/s00423-012-0998-5

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  • DOI: https://doi.org/10.1007/s00423-012-0998-5

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