Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice

• Published in: Scientific reports Vol. 6; no. 1; p. 28337
• Main Authors: Skarpengland, Tonje, Holm, Sverre, Scheffler, Katja, Gregersen, Ida, Dahl, Tuva B., Suganthan, Rajikala, Segers, Filip M., Østlie, Ingunn, Otten, Jeroen J. T., Luna, Luisa, Ketelhuth, Daniel F. J., Lundberg, Anna M., Neurauter, Christine G., Hildrestrand, Gunn, Skjelland, Mona, Bjørndal, Bodil, Svardal, Asbjørn M., Iversen, Per O., Hedin, Ulf, Nygård, Ståle, Olstad, Ole K., Krohg-Sørensen, Kirsten, Slupphaug, Geir, Eide, Lars, Kuśnierczyk, Anna, Folkersen, Lasse, Ueland, Thor, Berge, Rolf K., Hansson, Göran K., Biessen, Erik A. L., Halvorsen, Bente, Bjørås, Magnar, Aukrust, Pål
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.06.2016; Nature Publishing Group
• Subjects: 631/337/1427/1429; 692/4019/592; 692/699/75; Animals; Antigens, CD - genetics; Antigens, Differentiation, Myelomonocytic - genetics; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - prevention & control; Biobanks; Biochemistry; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA Damage; DNA Repair; Endodeoxyribonucleases - genetics; Endodeoxyribonucleases - metabolism; Genetic variance; Hospitals; Humanities and Social Sciences; Ischemia; Lipid Metabolism; Macrophages - metabolism; Males; Medical research; Medicin och hälsovetenskap; Medicine; Metabolism; Mice; Mice, Knockout, ApoE; Mitochondrial DNA; multidisciplinary; Myocardial infarction; N-Glycosyl Hydrolases - genetics; N-Glycosyl Hydrolases - metabolism; Oxidative Stress; Pathogenesis; Science; Science (multidisciplinary); Veins & arteries; Norway; Sweden
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep28337

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.