Journal article
Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice
Oslo University Hospital1
Maastricht University2
Karolinska University Hospital3
University of Bergen4
University of Oslo5
Norwegian University of Science and Technology6
Department of Systems Biology, Technical University of Denmark7
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark8
Integrative Systems Biology, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark9
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.
Language: | English |
---|---|
Publisher: | Nature Publishing Group |
Year: | 2016 |
Pages: | 28337 |
ISSN: | 20452322 |
Types: | Journal article |
DOI: | 10.1038/srep28337 |
ORCIDs: | Folkersen, Lasse |
Base excision repair Cardiovascular biology Cardiovascular diseases SDG 3 - Good Health and Well-being
Animals Antigens, CD Antigens, Differentiation, Myelomonocytic Atherosclerosis CD68 antigen, human DNA Damage DNA Repair Disease Models, Animal Endodeoxyribonucleases Lipid Metabolism Macrophages Mice Mice, Knockout, ApoE N-Glycosyl Hydrolases NEIL3 protein, human NEIL3 protein, mouse Oxidative Stress