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 Østlie; Jeroen J. T. Otten; Luisa Luna; Daniel F. J. Ketelhuth; Anna M. Lundberg; Christine G. Neurauter; Gunn Hildrestrand; Mona Skjelland; Bodil Bjørndal; Asbjørn M. Svardal; Per O. Iversen; Ulf Hedin; Ståle Nygård; Ole K. Olstad; Kirsten Krohg-Sorensen; Geir Slupphaug; Lars Eide; Anna Kusnierczyk; Lasse Folkersen; Thor Ueland; Rolf K. Berge; Göran K. Hansson; Erik A. L. Biessen; Bente Halvorsen; Magnar Bjørås; Pål 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 Østlie, Jeroen J. T. Otten, Luisa Luna, Daniel F. J. Ketelhuth, Anna M. Lundberg, Christine G. Neurauter, Gunn Hildrestrand, Mona Skjelland, Bodil Bjørndal, Asbjørn M. Svardal, Per O. Iversen, Ulf Hedin, Ståle NygårdOle K. Olstad, Kirsten Krohg-Sorensen, Geir Slupphaug, Lars Eide, Anna Kusnierczyk, Lasse Folkersen, Thor Ueland, Rolf K. Berge, Göran K. Hansson, Erik A. L. Biessen, Bente Halvorsen, Magnar Bjørås, Pål Aukrust

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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
Number of pages	13
ISSN	2045-2322
DOIs	https://doi.org/10.1038/srep28337
Publication status	Published - 2016

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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Keywords

Base excision repair
Cardiovascular biology
Cardiovascular diseases

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Skarpengland, T., Holm, S., Scheffler, K., Gregersen, I., Dahl, T. B., Suganthan, R., Segers, F. M., Østlie, I., Otten, J. J. T., Luna, L., Ketelhuth, D. F. J., Lundberg, A. M., Neurauter, C. G., Hildrestrand, G., Skjelland, M., Bjørndal, 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, [28337]. https://doi.org/10.1038/srep28337

Skarpengland, Tonje ; Holm, Sverre ; Scheffler, Katja ; Gregersen, Ida ; Dahl, Tuva B. ; Suganthan, Rajikala ; Segers, Filip M. ; Østlie, Ingunn ; Otten, Jeroen J. T. ; Luna, Luisa ; Ketelhuth, Daniel F. J. ; Lundberg, Anna M. ; Neurauter, Christine G. ; Hildrestrand, Gunn ; Skjelland, Mona ; Bjørndal, Bodil ; Svardal, Asbjørn M. ; Iversen, Per O. ; Hedin, Ulf ; Nygård, Ståle ; Olstad, Ole K. ; Krohg-Sorensen, Kirsten ; Slupphaug, Geir ; Eide, Lars ; Kusnierczyk, Anna ; Folkersen, Lasse ; Ueland, Thor ; Berge, Rolf K. ; Hansson, Göran K. ; Biessen, Erik A. L. ; Halvorsen, Bente ; Bjørås, Magnar ; Aukrust, Pål. / Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice. In: Scientific Reports. 2016 ; Vol. 6.

@article{a49310a36c05418f9ceaabb2d545f50f,

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.",

keywords = "Base excision repair, Cardiovascular biology, Cardiovascular diseases",

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 {\O}stlie 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 Bj{\o}rndal and Svardal, {Asbj{\o}rn M.} and Iversen, {Per O.} and Ulf Hedin and St{\aa}le Nyg{\aa}rd 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, {G{\"o}ran K.} and Biessen, {Erik A. L.} and Bente Halvorsen and Magnar Bj{\o}r{\aa}s and P{\aa}l Aukrust",

note = "This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/",

year = "2016",

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, Østlie, I, Otten, JJT, Luna, L, Ketelhuth, DFJ, Lundberg, AM, Neurauter, CG, Hildrestrand, G, Skjelland, M, Bjørndal, B, Svardal, AM, Iversen, PO, Hedin, U, Nygård, S, Olstad, OK, Krohg-Sorensen, K, Slupphaug, G, Eide, L, Kusnierczyk, A, Folkersen, L, Ueland, T, Berge, RK, Hansson, GK, Biessen, EAL, Halvorsen, B, Bjørås, 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

Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice. / Skarpengland, Tonje; Holm, Sverre; Scheffler, Katja; Gregersen, Ida; Dahl, Tuva B.; Suganthan, Rajikala; Segers, Filip M.; Østlie, Ingunn; Otten, Jeroen J. T.; Luna, Luisa; Ketelhuth, Daniel F. J.; Lundberg, Anna M.; Neurauter, Christine G.; Hildrestrand, Gunn; Skjelland, Mona; Bjørndal, Bodil; Svardal, Asbjørn M.; Iversen, Per O.; Hedin, Ulf; Nygård, Ståle; Olstad, Ole K.; Krohg-Sorensen, Kirsten; Slupphaug, Geir; Eide, Lars; Kusnierczyk, Anna; Folkersen, Lasse; Ueland, Thor; Berge, Rolf K.; Hansson, Göran K.; Biessen, Erik A. L.; Halvorsen, Bente; Bjørås, Magnar; Aukrust, Pål.

In: Scientific Reports, Vol. 6, 28337, 2016.

Research output: Contribution to journal › Journal article › Research › peer-review

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 - Østlie, 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 - Bjørndal, Bodil

AU - Svardal, Asbjørn M.

AU - Iversen, Per O.

AU - Hedin, Ulf

AU - Nygård, Ståle

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, Göran K.

AU - Biessen, Erik A. L.

AU - Halvorsen, Bente

AU - Bjørås, Magnar

AU - Aukrust, Pål

N1 - This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

PY - 2016

Y1 - 2016

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.

KW - Base excision repair

KW - Cardiovascular biology

KW - Cardiovascular diseases

U2 - 10.1038/srep28337

DO - 10.1038/srep28337

M3 - Journal article

C2 - 27328939

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 28337

ER -

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

Abstract

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Keywords

UN SDGs

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