Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-κB-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, Eoin P CumminsCormac T Taylor

Research output: Contribution to journalArticlepeer-review

Abstract

Hepatocyte death is an important contributing factor in a number of diseases of the liver. PHD1 confers hypoxic sensitivity upon transcription factors including the hypoxia inducible factor (HIF) and nuclear factor-kappaB (NF-κB). Reduced PHD1 activity is linked to decreased apoptosis. Here, we investigated 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 of pharmacologic hydroxylase inhibition. We hypothesize that PHD1 inhibition leads to altered expression of NF-κB-dependent genes resulting in reduced apoptosis. This study provides new information relating to the possible mechanism of therapeutic action of hydroxylase inhibitors that has been reported in pre-clinical models of intestinal and hepatic disease.

Original languageEnglish
Pages (from-to)579-86
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume474
Issue number3
Early online date27 Apr 2016
DOIs
Publication statusPublished - 3 Jun 2016

Keywords

  • Apoptosis
  • Hypoxia
  • NF-κB
  • Prolyl hydroxylase

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