title: ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?
abstract: BACKGROUND
  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.
  
  
  METHODS
  In this study we investigated the regulation of cholesterol biosynthesis in human dermal fibroblasts from PXE patients and healthy controls.
  
  
  RESULTS
  Gene 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.
  
  
  CONCLUSIONS
  Increased 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.
authors: Patricia
authors: P
authors: Kuzaj
authors: Joachim
authors: J
authors: Kuhn
authors: Mareike
authors: M
authors: Dabisch-Ruthe
authors: Isabel
authors: I
authors: Faust
authors: Christian
authors: C
authors: Götting
authors: Cornelius
authors: C
authors: Knabbe
authors: Herz- und Diabeteszentrum NRW, Institut für Laboratoriums- und Transfusionsmedizin, Universitätsklinik der Ruhr-Universität Bochum, Georgstraße 11, 32 545 Bad Oeynhausen, Germany. dhendig@hdz-nrw.de.
authors: Doris
authors: D
authors: Hendig
mesh_terms: D000328:Adult; D053898:Biosynthetic Pathways; D016022:Case-Control Studies; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D018389:Codon, Nonsense; D016895:Culture Media, Serum-Free; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism; D011561:Pseudoxanthoma Elasticum / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D002784:Cholesterol; D018389:Codon, Nonsense; D016895:Culture Media, Serum-Free; D006903:Hydroxymethylglutaryl CoA Reductases; D008074:Lipoproteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL; D012697:Serine Endopeptidases; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; C102029:ABCC6 protein, human; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; C472125:PCSK9 protein, human