학술논문
Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-κB-dependent manner.
Document Type
Article
Author
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; von Kriegsheim, Alex; Cummins, Eoin P.
Source
Subject
*PROLINE hydroxylase
*LIVER cells
*APOPTOSIS
*NF-kappa B
*CELL death
*LIVER diseases
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Language
ISSN
0006-291X
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. [ABSTRACT FROM AUTHOR]