Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice

Abstract Genetic studies link adenosine triphosphate-binding cassette transporter C6 (ABCC6) mutations to pseudoxanthoma elasticum (PXE). ABCC6 sequence variations are correlated with altered HDL cholesterol levels and an elevated risk of coronary artery diseases. However, the role of ABCC6 in chole...

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Autores principales:	Bettina Ibold, Janina Tiemann, Isabel Faust, Uta Ceglarek, Julia Dittrich, Theo G. M. F. Gorgels, Arthur A. B. Bergen, Olivier Vanakker, Matthias Van Gils, Cornelius Knabbe, Doris Hendig
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9a7807a95b5a4947b9f5a712694318ad
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spelling	oai:doaj.org-article:9a7807a95b5a4947b9f5a712694318ad2021-12-02T13:50:49ZGenetic deletion of Abcc6 disturbs cholesterol homeostasis in mice10.1038/s41598-021-81573-12045-2322https://doaj.org/article/9a7807a95b5a4947b9f5a712694318ad2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81573-1https://doaj.org/toc/2045-2322Abstract Genetic studies link adenosine triphosphate-binding cassette transporter C6 (ABCC6) mutations to pseudoxanthoma elasticum (PXE). ABCC6 sequence variations are correlated with altered HDL cholesterol levels and an elevated risk of coronary artery diseases. However, the role of ABCC6 in cholesterol homeostasis is not widely known. Here, we report reduced serum cholesterol and phytosterol levels in Abcc6-deficient mice, indicating an impaired sterol absorption. Ratios of cholesterol precursors to cholesterol were increased, confirmed by upregulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) expression, suggesting activation of cholesterol biosynthesis in Abcc6 −/− mice. We found that cholesterol depletion was accompanied by a substantial decrease in HDL cholesterol mediated by lowered ApoA-I and ApoA-II protein levels and not by inhibited lecithin-cholesterol transferase activity. Additionally, higher proprotein convertase subtilisin/kexin type 9 (Pcsk9) serum levels in Abcc6 −/− mice and PXE patients and elevated ApoB level in knockout mice were observed, suggesting a potentially altered very low-density lipoprotein synthesis. Our results underline the role of Abcc6 in cholesterol homeostasis and indicate impaired cholesterol metabolism as an important pathomechanism involved in PXE manifestation.Bettina IboldJanina TiemannIsabel FaustUta CeglarekJulia DittrichTheo G. M. F. GorgelsArthur A. B. BergenOlivier VanakkerMatthias Van GilsCornelius KnabbeDoris HendigNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bettina Ibold Janina Tiemann Isabel Faust Uta Ceglarek Julia Dittrich Theo G. M. F. Gorgels Arthur A. B. Bergen Olivier Vanakker Matthias Van Gils Cornelius Knabbe Doris Hendig Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice
description	Abstract Genetic studies link adenosine triphosphate-binding cassette transporter C6 (ABCC6) mutations to pseudoxanthoma elasticum (PXE). ABCC6 sequence variations are correlated with altered HDL cholesterol levels and an elevated risk of coronary artery diseases. However, the role of ABCC6 in cholesterol homeostasis is not widely known. Here, we report reduced serum cholesterol and phytosterol levels in Abcc6-deficient mice, indicating an impaired sterol absorption. Ratios of cholesterol precursors to cholesterol were increased, confirmed by upregulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) expression, suggesting activation of cholesterol biosynthesis in Abcc6 −/− mice. We found that cholesterol depletion was accompanied by a substantial decrease in HDL cholesterol mediated by lowered ApoA-I and ApoA-II protein levels and not by inhibited lecithin-cholesterol transferase activity. Additionally, higher proprotein convertase subtilisin/kexin type 9 (Pcsk9) serum levels in Abcc6 −/− mice and PXE patients and elevated ApoB level in knockout mice were observed, suggesting a potentially altered very low-density lipoprotein synthesis. Our results underline the role of Abcc6 in cholesterol homeostasis and indicate impaired cholesterol metabolism as an important pathomechanism involved in PXE manifestation.
format	article
author	Bettina Ibold Janina Tiemann Isabel Faust Uta Ceglarek Julia Dittrich Theo G. M. F. Gorgels Arthur A. B. Bergen Olivier Vanakker Matthias Van Gils Cornelius Knabbe Doris Hendig
author_facet	Bettina Ibold Janina Tiemann Isabel Faust Uta Ceglarek Julia Dittrich Theo G. M. F. Gorgels Arthur A. B. Bergen Olivier Vanakker Matthias Van Gils Cornelius Knabbe Doris Hendig
author_sort	Bettina Ibold
title	Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice
title_short	Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice
title_full	Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice
title_fullStr	Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice
title_full_unstemmed	Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice
title_sort	genetic deletion of abcc6 disturbs cholesterol homeostasis in mice
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9a7807a95b5a4947b9f5a712694318ad
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Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice

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