Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner

Susan F Fitzpatrick, Zsolt Fábián, Bettina Schaible, Colin R Lenihan, Thomas Schwarzl, Javier Rodriguez, Xingnan Zheng, Zongwei Li, Murtaza M Tambuwala, Desmond G Higgins, Yvonne O'Meara, Craig Slattery, Mario C. Manresa, Peter Fraisl, Ulrike Bruning, Myriam Baes, Peter Carmeliet, Glen Doherty, Alex von Kriegsheim

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Abstract

Hepatocyte death is an important contributing factor in a number of diseases of the liver. PHD1confers hypoxic sensitivity upon transcription factors including the hypoxia inducible factor (HIF) andnuclear factor-kappaB (NF-κB). Reduced PHD1 activity is linked to decreased apoptosis. Here, weinvestigated the underlying mechanism(s) in hepatocytes. Basal NF-κB activity was elevated in PHD1-/- hepatocytes compared to wild type controls. ChIP-seq analysis confirmed enhanced binding of NF-κB to chromatin in regions proximal to the promoters of genes involved in the regulation of apoptosis.Inhibition of NF-κB (but not knock-out of HIF-1 or HIF-2) reversed the anti-apoptotic effects ofpharmacologic hydroxylase inhibition. We hypothesize that PHD1 inhibition leads to alteredexpression of NF-κB-dependent genes resulting in reduced apoptosis. This study provides newinformation relating to the possible mechanism of therapeutic action of hydroxylase inhibitors that hasbeen reported in pre-clinical models of intestinal and hepatic disease.
Original languageEnglish
Pages (from-to)579-586
JournalBiochemical and Biophysical Research Communications
Volume474
Issue number3
Early online date27 Apr 2016
DOIs
Publication statusE-pub ahead of print - 27 Apr 2016

Keywords

  • Prolyl hydroxylase
  • NF-κB
  • Apoptosis
  • Hypoxia

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    Fitzpatrick, S. F., Fábián, Z., Schaible, B., Lenihan, C. R., Schwarzl, T., Rodriguez, J., Zheng, X., Li, Z., Tambuwala, M. M., Higgins, D. G., O'Meara, Y., Slattery, C., Manresa, M. C., Fraisl, P., Bruning, U., Baes, M., Carmeliet, P., Doherty, G., & Kriegsheim, A. V. (2016). Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner. Biochemical and Biophysical Research Communications, 474(3), 579-586. https://doi.org/10.1016/j.bbrc.2016.04.085