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

Biochem Biophys Res Commun. 2016 Jun 3;474(3):579-586. doi: 10.1016/j.bbrc.2016.04.085. Epub 2016 Apr 27.

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.

Keywords: Apoptosis; Hypoxia; NF-κB; Prolyl hydroxylase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cell Hypoxia / physiology
  • Cell Line
  • Gene Expression Regulation, Enzymologic / physiology
  • HEK293 Cells
  • Hepatocytes / cytology*
  • Hepatocytes / physiology*
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism*
  • Mice
  • NF-kappa B / metabolism*
  • Procollagen-Proline Dioxygenase / metabolism*

Substances

  • NF-kappa B
  • PHD1 protein, mouse
  • Procollagen-Proline Dioxygenase
  • EGLN2 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases