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

doi:10.1016/j.bbrc.2016.04.085

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 language	English
Pages (from-to)	579-586
Journal	Biochemical and Biophysical Research Communications
Volume	474
Issue number	3
Early online date	27 Apr 2016
DOIs	https://doi.org/10.1016/j.bbrc.2016.04.085
Publication status	Published online - 27 Apr 2016

Keywords

Prolyl hydroxylase
NF-κB
Apoptosis
Hypoxia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-κB-dependent mannerAuthor Accepted Manuscript, 7.32 MB

http://www.sciencedirect.com/science/article/pii/S0006291X16305915?np=y

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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. Advance online publication. https://doi.org/10.1016/j.bbrc.2016.04.085

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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}",

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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

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

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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