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.
- Prolyl hydroxylase