title: Beyond LDL-C lowering: distinct molecular sphingolipids are good indicators of proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency.
abstract: OBJECTIVE
  Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been proposed to be a potential new therapeutic target for treatment of hypercholesterolaemia. However, little is known about the effects of PCSK9 inhibition on the lipidome.
  
  
  METHODS
  We performed molecular lipidomic analyses of plasma samples obtained from PCSK9-deficient mice, and serum of human carriers of a loss-of-function variant in the PCSK9 gene (R46L).
  
  
  RESULTS
  In both mouse and man, PCSK9 deficiency caused a decrease in several cholesteryl esters (CE) and short fatty acid chain containing sphingolipid species such as CE 16:0, glucosyl/galactosylceramide (Glc/GalCer) d18:1/16:0, and lactosylceramide (LacCer) d18:1/16:0. In mice, the changes in lipid concentrations were most prominent when animals were given regular chow diet. In man, a number of molecular lipid species was shown to decrease significantly even when LDL-cholesterol was non-significantly reduced by 10% only. Western diet attenuated the lipid lowering potency of PCSK9 deficiency in mice.
  
  
  CONCLUSIONS
  Plasma molecular lipid species may be utilized for characterizing novel compounds inhibiting PCSK9 and as sensitive efficacy markers of the PCSK9 inhibition.
authors.affiliation: Zora Biosciences, Biologinkuja 1, FI-02150 Espoo, Finland.
authors.forename: Minna T
authors.initials: MT
authors.lastname: Jänis
authors.forename: Kirill
authors.initials: K
authors.lastname: Tarasov
authors.forename: Hung Xuan
authors.initials: HX
authors.lastname: Ta
authors.forename: Matti
authors.initials: M
authors.lastname: Suoniemi
authors.forename: Kim
authors.initials: K
authors.lastname: Ekroos
authors.forename: Reini
authors.initials: R
authors.lastname: Hurme
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Hannu
authors.initials: H
authors.lastname: Päivä
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Kleber
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: Reijo
authors.initials: R
authors.lastname: Laaksonen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000172:deficiency* / Q000235:genetics; D011446:Prospective Studies; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics; D013107:Sphingolipids / Q000097:blood*
chemical_list: D015415:Biomarkers; D002788:Cholesterol Esters; D008078:Cholesterol, LDL; D013107:Sphingolipids; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases