OBJECTIVES: 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.
OBJECTIVES: 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: Juho-Pekka Karjalainen; Nina Mononen; Nina Hutri-Kähönen; Miikael Lehtimäki; Mika Hilvo; Dimple Kauhanen; Markus Juonala; Jorma Viikari; Mika Kähönen; Olli Raitakari; Reijo Laaksonen; Terho Lehtimäki Journal: J Lipid Res Date: 2019-07-03 Impact factor: 5.922
Authors: Reijo Laaksonen; Kim Ekroos; Marko Sysi-Aho; Mika Hilvo; Terhi Vihervaara; Dimple Kauhanen; Matti Suoniemi; Reini Hurme; Winfried März; Hubert Scharnagl; Tatjana Stojakovic; Efthymia Vlachopoulou; Marja-Liisa Lokki; Markku S Nieminen; Roland Klingenberg; Christian M Matter; Thorsten Hornemann; Peter Jüni; Nicolas Rodondi; Lorenz Räber; Stephan Windecker; Baris Gencer; Eva Ringdal Pedersen; Grethe S Tell; Ottar Nygård; Francois Mach; Juha Sinisalo; Thomas F Lüscher Journal: Eur Heart J Date: 2016-04-28 Impact factor: 29.983