title: Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice.
abstract: Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Recently, we showed that a genetic variant in the human DNA repair enzyme NEIL3 was associated with increased risk of myocardial infarction. Here, we explored the role of Neil3/NEIL3 in atherogenesis by both clinical and experimental approaches. Human carotid plaques revealed increased NEIL3 mRNA expression which significantly correlated with mRNA levels of the macrophage marker CD68. Apoe(-/-)Neil3(-/-) mice on high-fat diet showed accelerated plaque formation as compared to Apoe(-/-) mice, reflecting an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoe(-/-)Neil3(-/-) mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage.
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Tonje
authors.initials: T
authors.lastname: Skarpengland
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Sverre
authors.initials: S
authors.lastname: Holm
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Institute of Basic Medical Research, University of Oslo, Oslo, Norway.|Department of Informatics, University of Oslo, Oslo, Norway.
authors.forename: Katja
authors.initials: K
authors.lastname: Scheffler
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ida
authors.initials: I
authors.lastname: Gregersen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.
authors.forename: Tuva B
authors.initials: TB
authors.lastname: Dahl
authors.affiliation: Department of Microbiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Rajikala
authors.initials: R
authors.lastname: Suganthan
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Filip M
authors.initials: FM
authors.lastname: Segers
authors.affiliation: Department of Pathology,Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Ingunn
authors.initials: I
authors.lastname: Østlie
authors.affiliation: Department of Experimental Vascular Pathology, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Jeroen J T
authors.initials: JJ
authors.lastname: Otten
authors.affiliation: Department of Microbiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Luisa
authors.initials: L
authors.lastname: Luna
authors.affiliation: Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Daniel F J
authors.initials: DF
authors.lastname: Ketelhuth
authors.affiliation: Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Lundberg
authors.affiliation: Department of Microbiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Christine G
authors.initials: CG
authors.lastname: Neurauter
authors.affiliation: Department of Microbiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Gunn
authors.initials: G
authors.lastname: Hildrestrand
authors.affiliation: Department of Neurology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Mona
authors.initials: M
authors.lastname: Skjelland
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Bodil
authors.initials: B
authors.lastname: Bjørndal
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Asbjørn M
authors.initials: AM
authors.lastname: Svardal
authors.affiliation: Institute of Basic Medical Research, University of Oslo, Oslo, Norway.|Department of Hematology, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Department of Nutrition, University of Oslo, Oslo, Norway.
authors.forename: Per O
authors.initials: PO
authors.lastname: Iversen
authors.affiliation: Department of Surgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.affiliation: Department of Informatics, University of Oslo, Oslo, Norway.
authors.forename: Ståle
authors.initials: S
authors.lastname: Nygård
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital Ullevål, Oslo, Norway.
authors.forename: Ole K
authors.initials: OK
authors.lastname: Olstad
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Thoracic and Cardiovascular Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Krohg-Sørensen
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|PROMEC Core Facility for Proteomics and Metabolomics, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Slupphaug
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Medical Biochemistry, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|PROMEC Core Facility for Proteomics and Metabolomics, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuśnierczyk
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Copenhagen, Denmark.
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Berge
authors.affiliation: Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.affiliation: Department of Experimental Vascular Pathology, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Microbiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.|PROMEC Core Facility for Proteomics and Metabolomics, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.|Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004249:DNA Damage; D004260:DNA Repair; D004195:Disease Models, Animal; D004706:Endodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D000074085:Mice, Knockout, ApoE; D009699:N-Glycosyl Hydrolases / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D004706:Endodeoxyribonucleases; D009699:N-Glycosyl Hydrolases; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C540052:NEIL3 protein, mouse; C468764:NEIL3 protein, human