Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice

Bettina Ibold,Julia Dittrich,Doris Hendig,Cornelius Knabbe,Matthias Van Gils,Olivier Vanakker,Janina Tiemann,Arthur A B Bergen,Uta Ceglarek,Isabel Faust,Theo G M F Gorgels

doi:10.1038/s41598-021-81573-1

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.

Highlights

Genetic studies link adenosine triphosphate-binding cassette transporter C6 (ABCC6) mutations to pseudoxanthoma elasticum (PXE)
Human genetic studies have demonstrated that diverse sequence variations of well-known genes, such as LIPC, ABCA1 or even ABCC6, which cause PXE, are not disease-causing, but associated with decreased HDL cholesterol[6,7,20,21]
This association could be directly related to a higher cardiovascular risk in PXE patients

Summary

Introduction

Genetic studies link adenosine triphosphate-binding cassette transporter C6 (ABCC6) mutations to pseudoxanthoma elasticum (PXE). Mutations in the adenosine triphosphate-binding cassette transporter C6 (ABCC6) gene are responsible for pseudoxanthoma elasticum (PXE), a metabolic disease, hallmarked by a progressive elastic fiber calcification of the skin, eyes and cardiovascular system. We used 6- and 12-month old Abcc6−/− mice to reflect an early and a late disease stage of PXE to study the effects of an Abcc[6] deficiency on cholesterol homeostasis. We found reduced HDL and total cholesterol levels in the serum of 12-month-old Abcc6−/− mice. These Abcc6−/− mice showed consistently lower ApoA-I and ApoA-II levels and reduced phytosterol amounts in their serum These results indicate that the ABC-transporter Abcc[6] plays a relevant role in cholesterol metabolism and add new insights into the pathophysiology of PXE

Methods

Results

Conclusion