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

Sci Rep. 2016 Jun 22:6:28337. doi: 10.1038/srep28337.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, Differentiation, Myelomonocytic / genetics
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / prevention & control*
  • DNA Damage
  • DNA Repair*
  • Disease Models, Animal
  • Endodeoxyribonucleases / genetics*
  • Endodeoxyribonucleases / metabolism
  • Lipid Metabolism*
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout, ApoE
  • N-Glycosyl Hydrolases / genetics*
  • N-Glycosyl Hydrolases / metabolism
  • Oxidative Stress

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • Endodeoxyribonucleases
  • NEIL3 protein, mouse
  • N-Glycosyl Hydrolases
  • NEIL3 protein, human