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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 and Kriegsheim, Alex von (2016) Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner. Biochemical and Biophysical Research Communications, 474 (3). pp. 579-586. [Journal article]

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

DOI: 10.1016/j.bbrc.2016.04.085

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.

Item Type:Journal article
Keywords:Prolyl hydroxylase; NF-κB; Apoptosis; Hypoxia
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Pharmacy & Pharmaceutical Sciences
ID Code:34565
Deposited By: Dr Murtaza Tambuwala
Deposited On:03 May 2016 08:15
Last Modified:17 Oct 2017 16:23

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