title: Deficiency of the oxygen sensor prolyl hydroxylase 1 attenuates hypercholesterolaemia, atherosclerosis, and hyperglycaemia.
abstract: Normalization of hypercholesterolaemia, inflammation, hyperglycaemia, and obesity are main desired targets to prevent cardiovascular clinical events. Here we present a novel regulator of cholesterol metabolism, which simultaneously impacts on glucose intolerance and inflammation.
  
  
  
  Mice deficient for oxygen sensor HIF-prolyl hydroxylase 1 (PHD1) were backcrossed onto an atherogenic low-density lipoprotein receptor (LDLR) knockout background and atherosclerosis was studied upon 8 weeks of western-type diet. PHD1-/-LDLR-/-mice presented a sharp reduction in VLDL and LDL plasma cholesterol levels. In line, atherosclerotic plaque development, as measured by plaque area, necrotic core expansion and plaque stage was hampered in PHD1-/-LDLR-/-mice. Mechanistically, cholesterol-lowering in PHD1 deficient mice was a result of enhanced cholesterol excretion from blood to intestines and ultimately faeces. Additionally, flow cytometry of whole blood of these mice revealed significantly reduced counts of leucocytes and particularly of Ly6Chighpro-inflammatory monocytes. In addition, when studying PHD1-/-in diet-induced obesity (14 weeks high-fat diet) mice were less glucose intolerant when compared with WT littermate controls.
  
  
  
  Overall, PHD1 knockout mice display a metabolic phenotype that generally is deemed protective for cardiovascular disease. Future studies should focus on the efficacy, safety, and gender-specific effects of PHD1 inhibition in humans, and unravel the molecular actors responsible for PHD1-driven, likely intestinal, and regulation of cholesterol metabolism.
authors.affiliation: Department of Pathology, CARIM, MUMC, P. Debyelaan 25, Maastricht 6229 HX, The Netherlands.
authors.forename: Elke
authors.initials: E
authors.lastname: Marsch
authors.affiliation: Department of Pathology, CARIM, MUMC, P. Debyelaan 25, Maastricht 6229 HX, The Netherlands.
authors.forename: Jasper A F
authors.initials: JA
authors.lastname: Demandt
authors.affiliation: Department of Pathology, CARIM, MUMC, P. Debyelaan 25, Maastricht 6229 HX, The Netherlands.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Theelen
authors.affiliation: Department of Pathology, CARIM, MUMC, P. Debyelaan 25, Maastricht 6229 HX, The Netherlands.
authors.forename: Bibian M E
authors.initials: BM
authors.lastname: Tullemans
authors.affiliation: Department of Internal Medicine, CARIM, Maastricht University, Maastricht, The Netherlands.
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Wouters
authors.affiliation: Department of Human Biology, Maastricht University, Maastricht, The Netherlands.|Department of Medicine, Division of Endocrinology and Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands.
authors.forename: Mariëtte R
authors.initials: MR
authors.lastname: Boon
authors.affiliation: Department of Pediatrics/Laboratory Medicine, UMCG, Groningen, The Netherlands.
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.affiliation: Department of Pathology, CARIM, MUMC, P. Debyelaan 25, Maastricht 6229 HX, The Netherlands.|Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands.|Department of Medical Biochemistry, AMC, Amsterdam, The Netherlands.
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.affiliation: Department of Radiation Oncology, MUMC, Maastricht, The Netherlands.
authors.forename: Ludwig J
authors.initials: LJ
authors.lastname: Dubois
authors.affiliation: Department of Clinical Chemistry, MUMC, Maastricht, The Netherlands.
authors.forename: Steven J R
authors.initials: SJ
authors.lastname: Meex
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: ISIS Pharmaceuticals, Inc., Carlsbad, USA.
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.affiliation: Department of Medicine, NYU, New York, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: Department of Pathology, CARIM, MUMC, P. Debyelaan 25, Maastricht 6229 HX, The Netherlands.|Institute for Cardiovascular Research, RWTH Aachen University, Aachen, Germany.
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: Department of Pathology, AMC, Amsterdam, The Netherlands.
authors.forename: Mat J A P
authors.initials: MJ
authors.lastname: Daemen
authors.affiliation: Department of Medicine, Division of Endocrinology and Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands.
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Department of Pediatrics/Laboratory Medicine, UMCG, Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Department of Pathology, CARIM, MUMC, P. Debyelaan 25, Maastricht 6229 HX, The Netherlands judith.sluimer@maastrichtuniversity.nl.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Sluimer
mesh_terms: D000818:Animals; D050197:Atherosclerosis; D004195:Disease Models, Animal; D006937:Hypercholesterolemia; D006943:Hyperglycemia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen; D064828:Prolyl Hydroxylases; D011973:Receptors, LDL
chemical_list: D011973:Receptors, LDL; D064828:Prolyl Hydroxylases; D010100:Oxygen
keywords: Atherosclerosis; Cholesterol and lipids; Hyperglycaemia; Inflammation; Oxygen sensor