| First Author | Fitzpatrick SF | Year | 2016 |
| Journal | Biochem Biophys Res Commun | Volume | 474 |
| Issue | 3 | Pages | 579-586 |
| PubMed ID | 27130823 | Mgi Jnum | J:235380 |
| Mgi Id | MGI:5796217 | Doi | 10.1016/j.bbrc.2016.04.085 |
| Citation | Fitzpatrick SF, et al. (2016) Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kappaB-dependent manner. Biochem Biophys Res Commun 474(3):579-86 |
| abstractText | 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-kappaB). Reduced PHD1 activity is linked to decreased apoptosis. Here, we investigated the underlying mechanism(s) in hepatocytes. Basal NF-kappaB activity was elevated in PHD1(-/-) hepatocytes compared to wild type controls. ChIP-seq analysis confirmed enhanced binding of NF-kappaB to chromatin in regions proximal to the promoters of genes involved in the regulation of apoptosis. Inhibition of NF-kappaB (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-kappaB-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. |
