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

Research output: Contribution to journalArticle

15 Citations (Scopus)
16 Downloads (Pure)

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

Fingerprint

Prolyl Hydroxylases
NF-kappa B
Hepatocytes
Apoptosis
Mixed Function Oxygenases
Genes
Hypoxia-Inducible Factor 1
Intestinal Diseases
Liver
Chromatin
Liver Diseases
Transcription Factors
Therapeutics

Keywords

  • Prolyl hydroxylase
  • NF-κB
  • Apoptosis
  • Hypoxia

Cite this

Fitzpatrick, S. F., Fábián, Z., Schaible, B., Lenihan, C. R., Schwarzl, T., Rodriguez, J., ... 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
Fitzpatrick, Susan F ; Fábián, Zsolt ; Schaible, Bettina ; Lenihan, Colin R ; Schwarzl, Thomas ; Rodriguez, Javier ; Zheng, Xingnan ; Li, Zongwei ; Tambuwala, Murtaza M ; Higgins, Desmond G ; O'Meara, Yvonne ; Slattery, Craig ; Manresa, Mario C. ; Fraisl, Peter ; Bruning, Ulrike ; Baes, Myriam ; Carmeliet, Peter ; Doherty, Glen ; Kriegsheim, Alex von. / Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner. In: Biochemical and Biophysical Research Communications. 2016 ; Vol. 474, No. 3. pp. 579-586.
@article{8fd8926230bc43ec88baa1ed11843fc2,
title = "Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner",
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.",
keywords = "Prolyl hydroxylase, NF-κB, Apoptosis, Hypoxia",
author = "Fitzpatrick, {Susan F} and Zsolt F{\'a}bi{\'a}n and Bettina Schaible and Lenihan, {Colin R} and Thomas Schwarzl and Javier Rodriguez and Xingnan Zheng and Zongwei Li and Tambuwala, {Murtaza M} and Higgins, {Desmond G} and Yvonne O'Meara and Craig Slattery and Manresa, {Mario C.} and Peter Fraisl and Ulrike Bruning and Myriam Baes and Peter Carmeliet and Glen Doherty and Kriegsheim, {Alex von}",
year = "2016",
month = "4",
day = "27",
doi = "10.1016/j.bbrc.2016.04.085",
language = "English",
volume = "474",
pages = "579--586",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Elsevier",
number = "3",

}

Fitzpatrick, SF, Fábián, Z, Schaible, B, Lenihan, CR, Schwarzl, T, Rodriguez, J, Zheng, X, Li, Z, Tambuwala, MM, Higgins, DG, O'Meara, Y, Slattery, C, Manresa, MC, Fraisl, P, Bruning, U, Baes, M, Carmeliet, P, Doherty, G & Kriegsheim, AV 2016, 'Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner', Biochemical and Biophysical Research Communications, vol. 474, no. 3, pp. 579-586. https://doi.org/10.1016/j.bbrc.2016.04.085

Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner. / Fitzpatrick, Susan F; Fábián, Zsolt; Schaible, Bettina; Lenihan, Colin R; Schwarzl, Thomas; Rodriguez, Javier; Zheng, Xingnan; Li, Zongwei; Tambuwala, Murtaza M; Higgins, Desmond G; O'Meara, Yvonne; Slattery, Craig; Manresa, Mario C.; Fraisl, Peter; Bruning, Ulrike; Baes, Myriam; Carmeliet, Peter; Doherty, Glen; Kriegsheim, Alex von.

In: Biochemical and Biophysical Research Communications, Vol. 474, No. 3, 27.04.2016, p. 579-586.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner

AU - Fitzpatrick, Susan F

AU - Fábián, Zsolt

AU - Schaible, Bettina

AU - Lenihan, Colin R

AU - Schwarzl, Thomas

AU - Rodriguez, Javier

AU - Zheng, Xingnan

AU - Li, Zongwei

AU - Tambuwala, Murtaza M

AU - Higgins, Desmond G

AU - O'Meara, Yvonne

AU - Slattery, Craig

AU - Manresa, Mario C.

AU - Fraisl, Peter

AU - Bruning, Ulrike

AU - Baes, Myriam

AU - Carmeliet, Peter

AU - Doherty, Glen

AU - Kriegsheim, Alex von

PY - 2016/4/27

Y1 - 2016/4/27

N2 - 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.

AB - 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.

KW - Prolyl hydroxylase

KW - NF-κB

KW - Apoptosis

KW - Hypoxia

U2 - 10.1016/j.bbrc.2016.04.085

DO - 10.1016/j.bbrc.2016.04.085

M3 - Article

VL - 474

SP - 579

EP - 586

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 3

ER -