title: Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-κB-dependent manner.
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.
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Belfield, Dublin 4 Ireland.
authors.forename: Susan F
authors.initials: SF
authors.lastname: Fitzpatrick
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Belfield, Dublin 4 Ireland.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Fábián
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Belfield, Dublin 4 Ireland.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schaible
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Belfield, Dublin 4 Ireland.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Lenihan
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Belfield, Dublin 4 Ireland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzl
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: Javier
authors.initials: J
authors.lastname: Rodriguez
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Xingnan
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, BT52 1SA, Northern Ireland, UK.
authors.forename: Murtaza M
authors.initials: MM
authors.lastname: Tambuwala
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Belfield, Dublin 4 Ireland.
authors.forename: Desmond G
authors.initials: DG
authors.lastname: Higgins
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Belfield, Dublin 4 Ireland.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: O'Meara
authors.affiliation: School of Biomolecular and Biomedical Science, The Conway Institute, University College Dublin, Belfield, Dublin 4 Ireland.
authors.forename: Craig
authors.initials: C
authors.lastname: Slattery
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Belfield, Dublin 4 Ireland.
authors.forename: Mario C
authors.initials: MC
authors.lastname: Manresa
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, University of Leuven, Vesalius Research Center, VIB, B-3000, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Fraisl
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, University of Leuven, Vesalius Research Center, VIB, B-3000, Belgium.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bruning
authors.affiliation: Laboratory for Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Baes
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, University of Leuven, Vesalius Research Center, VIB, B-3000, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, University of Leuven, Vesalius Research Center, VIB, B-3000, Belgium.
authors.forename: Glen
authors.initials: G
authors.lastname: Doherty
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: Alex
authors.initials: A
authors.lastname: von Kriegsheim
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Belfield, Dublin 4 Ireland.
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Cummins
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Belfield, Dublin 4 Ireland. Electronic address: cormac.taylor@ucd.ie.
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; C522721:PHD1 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: Apoptosis; Hypoxia; NF-κB; Prolyl hydroxylase