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

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

Biochem Biophys Res Commun. 2016 Apr 26;

Authors: 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, von Kriegsheim A, Cummins EP, Taylor CT

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.

PMID: 27130823 [PubMed - as supplied by publisher]

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