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

Tonje Skarpengland; Sverre Holm; Katja Scheffler; Ida Gregersen; Tuva B. Dahl; Rajikala Suganthan; Filip M. Segers; Ingunn Ostlie; Jeroen J. T. Otten; Luisa Luna; Daniel F. J. Ketelhuth; Anna M. Lundberg; Christine G. Neurauter; Gunn Hildrestrand; Mona Skjelland; Bodil Bjorndal; Asbjorn M. Svardal; Per O. Iversen; Ulf Hedin; Stale Nygard; Ole K. Olstad; Kirsten Krohg-Sorensen; Geir Slupphaug; Lars Eide; Anna Kusnierczyk; Lasse Folkersen; Thor Ueland; Rolf K. Berge; Goran K. Hansson; Erik A. L. Biessen; Bente Halvorsen; Magnar Bjoras; Pal Aukrust

doi:10.1038/srep28337

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

Tonje Skarpengland, Sverre Holm, Katja Scheffler, Ida Gregersen, Tuva B. Dahl, Rajikala Suganthan, Filip M. Segers, Ingunn Ostlie, Jeroen J. T. Otten, Luisa Luna, Daniel F. J. Ketelhuth, Anna M. Lundberg, Christine G. Neurauter, Gunn Hildrestrand, Mona Skjelland, Bodil Bjorndal, Asbjorn M. Svardal, Per O. Iversen, Ulf Hedin, Stale NygardOle K. Olstad, Kirsten Krohg-Sorensen, Geir Slupphaug, Lars Eide, Anna Kusnierczyk, Lasse Folkersen, Thor Ueland, Rolf K. Berge, Goran K. Hansson, Erik A. L. Biessen, Bente Halvorsen^*, Magnar Bjoras, Pal Aukrust

^*Corresponding author for this work

Pathologie

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	28337
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep28337
Publication status	Published - 22 Jun 2016

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10.1038/srep28337Licence: CC BY

Cite this

Skarpengland, T., Holm, S., Scheffler, K., Gregersen, I., Dahl, T. B., Suganthan, R., Segers, F. M., Ostlie, I., Otten, J. J. T., Luna, L., Ketelhuth, D. F. J., Lundberg, A. M., Neurauter, C. G., Hildrestrand, G., Skjelland, M., Bjorndal, B., Svardal, A. M., Iversen, P. O., Hedin, U., ... Aukrust, P. (2016). Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice. Scientific Reports, 6, Article 28337. https://doi.org/10.1038/srep28337

@article{9abc46014adc44ddadd65d58da9394c5,

title = "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.",

author = "Tonje Skarpengland and Sverre Holm and Katja Scheffler and Ida Gregersen and Dahl, {Tuva B.} and Rajikala Suganthan and Segers, {Filip M.} and Ingunn Ostlie and Otten, {Jeroen J. T.} and Luisa Luna and Ketelhuth, {Daniel F. J.} and Lundberg, {Anna M.} and Neurauter, {Christine G.} and Gunn Hildrestrand and Mona Skjelland and Bodil Bjorndal and Svardal, {Asbjorn M.} and Iversen, {Per O.} and Ulf Hedin and Stale Nygard and Olstad, {Ole K.} and Kirsten Krohg-Sorensen and Geir Slupphaug and Lars Eide and Anna Kusnierczyk and Lasse Folkersen and Thor Ueland and Berge, {Rolf K.} and Hansson, {Goran K.} and Biessen, {Erik A. L.} and Bente Halvorsen and Magnar Bjoras and Pal Aukrust",

year = "2016",

month = jun,

day = "22",

doi = "10.1038/srep28337",

language = "English",

volume = "6",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

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Skarpengland, T, Holm, S, Scheffler, K, Gregersen, I, Dahl, TB, Suganthan, R, Segers, FM, Ostlie, I, Otten, JJT, Luna, L, Ketelhuth, DFJ, Lundberg, AM, Neurauter, CG, Hildrestrand, G, Skjelland, M, Bjorndal, B, Svardal, AM, Iversen, PO, Hedin, U, Nygard, S, Olstad, OK, Krohg-Sorensen, K, Slupphaug, G, Eide, L, Kusnierczyk, A, Folkersen, L, Ueland, T, Berge, RK, Hansson, GK, Biessen, EAL, Halvorsen, B, Bjoras, M & Aukrust, P 2016, 'Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice', Scientific Reports, vol. 6, 28337. https://doi.org/10.1038/srep28337

TY - JOUR

T1 - Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice

AU - Skarpengland, Tonje

AU - Holm, Sverre

AU - Scheffler, Katja

AU - Gregersen, Ida

AU - Dahl, Tuva B.

AU - Suganthan, Rajikala

AU - Segers, Filip M.

AU - Ostlie, Ingunn

AU - Otten, Jeroen J. T.

AU - Luna, Luisa

AU - Ketelhuth, Daniel F. J.

AU - Lundberg, Anna M.

AU - Neurauter, Christine G.

AU - Hildrestrand, Gunn

AU - Skjelland, Mona

AU - Bjorndal, Bodil

AU - Svardal, Asbjorn M.

AU - Iversen, Per O.

AU - Hedin, Ulf

AU - Nygard, Stale

AU - Olstad, Ole K.

AU - Krohg-Sorensen, Kirsten

AU - Slupphaug, Geir

AU - Eide, Lars

AU - Kusnierczyk, Anna

AU - Folkersen, Lasse

AU - Ueland, Thor

AU - Berge, Rolf K.

AU - Hansson, Goran K.

AU - Biessen, Erik A. L.

AU - Halvorsen, Bente

AU - Bjoras, Magnar

AU - Aukrust, Pal

PY - 2016/6/22

Y1 - 2016/6/22

N2 - 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.

AB - 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.

U2 - 10.1038/srep28337

DO - 10.1038/srep28337

M3 - Article

C2 - 27328939

SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

M1 - 28337

ER -