ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?

Patricia Kuzaj,Doris Hendig,Joachim Kuhn,Christian Götting,Cornelius Knabbe,Mareike Dabisch-Ruthe,Isabel Faust

doi:10.1186/1476-511x-13-118

Patricia Kuzaj, Doris Hendig + Show 5 more

Open Access

https://doi.org/10.1186/1476-511x-13-118

Copy DOI

Abstract

BackgroundDysregulations in cholesterol and lipid metabolism have been linked to human diseases like hypercholesterolemia, atherosclerosis or the metabolic syndrome. Many ABC transporters are involved in trafficking of metabolites derived from these pathways. Pseudoxanthoma elasticum (PXE), an autosomal-recessive disease caused by ABCC6 mutations, is characterized by atherogenesis and soft tissue calcification.MethodsIn this study we investigated the regulation of cholesterol biosynthesis in human dermal fibroblasts from PXE patients and healthy controls.ResultsGene expression analysis of 84 targets indicated dysregulations in cholesterol metabolism in PXE fibroblasts. Transcript levels of ABCC6 were strongly increased in lipoprotein-deficient serum (LPDS) and under serum starvation in healthy controls. For the first time, increased HMG CoA reductase activities were found in PXE fibroblasts. We further observed strongly elevated transcript and protein levels for the proprotein convertase subtilisin/kexin type 9 (PCSK9), as well as a significant reduction in APOE mRNA expression in PXE.ConclusionIncreased cholesterol biosynthesis, elevated PCSK9 levels and reduced APOE mRNA expression newly found in PXE fibroblasts could enforce atherogenesis and cardiovascular risk in PXE patients. Moreover, the increase in ABCC6 expression accompanied by the induction of cholesterol biosynthesis supposes a functional role for ABCC6 in human lipoprotein and cholesterol homeostasis.

Highlights

Dysregulations in cholesterol and lipid metabolism have been linked to human diseases like hypercholesterolemia, atherosclerosis or the metabolic syndrome
Relative mRNA expression of proprotein convertase subtilisin/ kexin type 9 (PCSK9) exhibited a 46-fold increase in Pseudoxanthoma elasticum (PXE) fibroblasts (p < 0.04) compared to healthy controls, whereas no differences were found between siRNAtransfected cells
2.4-fold elevation of transmembrane 7 superfamily member 2 (TM7SF2) mRNA level in PXE cells revealed statistical significance (p < 0.04), which was confirmed by trend with Small-interfering RNA (siRNA) transfection

Summary

Introduction

Dysregulations in cholesterol and lipid metabolism have been linked to human diseases like hypercholesterolemia, atherosclerosis or the metabolic syndrome. Many ABC transporters are involved in trafficking of metabolites derived from these pathways. Pseudoxanthoma elasticum (PXE), an autosomal-recessive disease caused by ABCC6 mutations, is characterized by atherogenesis and soft tissue calcification. Many ABC transporters are involved in trafficking of metabolites derived from lipid or cholesterol biosynthesis, e.g. sterols, bile acids, phospholipids, or sphingolipids [3]. Genetic mutations in ABC transporters have been linked to various human diseases [2,3], like Dubin–Johnson syndrome (ABCC2), Tangier disease (ABCA1), or Pseudoxanthoma elasticum (ABCC6). Up to 350 causative genetic mutations have been found in ABCC6 [6]

Methods

Results

Discussion

Conclusion