Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice
Skarpengland, Tonje; Holm, Sverre; Scheffler, Katja; Gregersen, Ida; Dahl, Tuva Børresdatter; Suganthan, Rajikala; Segers, Filip; Østlie, Ingunn; Otten, Jeroen J.T.; Gomez, Luisa Fernanda Luna; Ketelhuth, Daniel F.J.; Lundberg, Anna M.; Neurauter, Christine Gran; Hildrestrand, Gunn Annette; Skjelland, Mona; Bjørndal, Bodil; Svardal, Asbjørn M.; Iversen, Per Ole; Hedin, Ulf; Nygård, Ståle; Olstad, Ole Kristoffer; Krohg-Sørensen, Kirsten; Slupphaug, Geir; Eide, Lars; Kusnierczyk, Anna; Folkersen, Lasse; Ueland, Thor; Berge, Rolf Kristian; Hansson, Göran K.; Biessen, Erik A.L.; Halvorsen, Bente; Bjørås, Magnar; Aukrust, Pål
Journal article, Peer reviewed
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OriginalversjonScientific Reports. 2016, 6, 28337. 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.