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 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

^*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

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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",

}

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 -

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

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