Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice

B. Ibold, J. Tiemann, I. Faust, U. Ceglarek, J. Dittrich, T.G.M.F. Gorgels, A.A.B. Bergen, O. Vanakker, M. Van Gils, C. Knabbe, D. Hendig*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Web of Science)

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.
Original languageEnglish
Article number2137
Number of pages13
JournalScientific Reports
Volume11
Issue number1
DOIs
Publication statusPublished - 22 Jan 2021

Keywords

  • artery
  • bisphosphonates
  • ectopic mineralization
  • expression
  • high-density-lipoprotein
  • mouse model
  • plant sterols
  • plasma
  • pseudoxanthoma elasticum
  • quantification
  • PSEUDOXANTHOMA ELASTICUM
  • QUANTIFICATION
  • HIGH-DENSITY-LIPOPROTEIN
  • BISPHOSPHONATES
  • PLASMA
  • MOUSE MODEL
  • ECTOPIC MINERALIZATION
  • PLANT STEROLS
  • ARTERY
  • EXPRESSION

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