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.

Subtypes identification on heart failure with preserved ejection fraction via network enhancement fusion using multi-omics data

“…In DEmRNAs, heart failure patients had elevated myocardia NEIL3 expression. NEIL3 regulated LDL-C and HDL-C levels and was associated with traditional cardiovascular risk factors [32] , [33] . The expression level of MMP13 was significantly increased while the expression of VEGF was significantly decreased in the high-risk group.…”

Mitochondrial DNA Integrity: Role in Health and Disease

“…Chronic high-fat diet further impaired metabolic function in these mice, secondary to an increase in mtDNA deletions and reduced mitochondrial protein content [118,141]. Similarly, engineered deletion of NEIL3 has been recently shown to increase susceptibility to atherosclerosis and increased size of atherosclerotic plaques in hypercholesterolemic mice deficient for the apolipoprotein, APOE3 [205]. The role of mitochondrial NEIL1 vs. the nuclear form of the enzyme in mediating metabolic phenotypes has not yet been determined, and NEIL3 does not have any reported mitochondrial localization.…”

Formation and processing of DNA damage substrates for the hNEIL enzymes

“…NEIL3 is also a required host factor for HIV replication [228]. Further, Neil3 was found to promote neurogenesis induced by hypoxia-ischemia [229], to regulate lipid metabolism preventing atherosclerosis [230], and to function during development prior to implantation [227]. Knockdown of Neil3 and Ogg1 in mice decreases embryonic neural stem cell differentiation [231].…”