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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.

SUBMITTER: Skarpengland T 

PROVIDER: S-EPMC4916448 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Skarpengland Tonje T   Holm Sverre S   Scheffler Katja K   Gregersen Ida I   Dahl Tuva B TB   Suganthan Rajikala R   Segers Filip M FM   Østlie Ingunn I   Otten Jeroen J T JJ   Luna Luisa L   Ketelhuth Daniel F J DF   Lundberg Anna M AM   Neurauter Christine G CG   Hildrestrand Gunn G   Skjelland Mona M   Bjørndal Bodil B   Svardal Asbjørn M AM   Iversen Per O PO   Hedin Ulf U   Nygård Ståle S   Olstad Ole K OK   Krohg-Sørensen Kirsten K   Slupphaug Geir G   Eide Lars L   Kuśnierczyk Anna A   Folkersen Lasse L   Ueland Thor T   Berge Rolf K RK   Hansson Göran K GK   Biessen Erik A L EA   Halvorsen Bente B   Bjørås Magnar M   Aukrust Pål P  

Scientific reports 20160622


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  ...[more]

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