Mikaël Croyal1,2, Valentin Blanchard3, Khadija Ouguerram1,2, Maud Chétiveaux4, Léa Cabioch5, Thomas Moyon2, Stéphanie Billon-Crossouard1,2, Audrey Aguesse1,2, Karine Bernardeau6, Cédric Le May4, Laurent Flet7, Gilles Lambert3, Samy Hadjadj8, Bertrand Cariou8, Michel Krempf1,2,9, Estelle Nobécourt-Dupuy10. 1. From the NUN, INRA, CHU Nantes, UMR 1280, PhAN, IMAD, CRNH-O, France (M. Croyal, K.O., S.B.-C., A.A., M.K.). 2. CRNH-O Mass Spectrometry Core Facility, F-44000 Nantes, France (M. Croyal, K.O., T.M., S.B.-C., A.A., M.K.). 3. Université de La Réunion, INSERM, UMR 1188 Diabète athérothrombose Réunion Océan Indien (DéTROI), Plateforme CYROI, Saint-Denis de La Réunion, France (V.B., G.L.). 4. L'institut du thorax, INSERM, CNRS, University of Nantes, France (M. Chétiveaux, C.L.M.). 5. Biogenouest-Corsaire platform, Saint Gilles, France (L.C.). 6. P2R «Production de protéines recombinantes», CRCINA, SFR-Santé, INSERM, CNRS, UNIV Nantes, CHU Nantes, France (K.B.). 7. Pharmacy Department, Nantes University Hospital, France (L.F.). 8. L'institut du thorax, INSERM, CNRS, University of Nantes, CHU Nantes, France (S.H., B.C.). 9. ELSAN, clinique Bretéché, Nantes, France (M.K.). 10. Nephrology Department, CHU Saint-Pierre, La Réunion, France (E.N.-D.).
Abstract
OBJECTIVE: To clarify the association between PCSK9 (proprotein convertase subtilisin/kexin type 9) and Lp(a) (lipoprotein [a]), we studied Lp(a) kinetics in patients with loss-of-function and gain-of-function PCSK9 mutations and in patients in whom extended-release niacin reduced Lp(a) and PCSK9 concentrations. Approach and Results: Six healthy controls, 9 heterozygous patients with familial hypercholesterolemia (5 with low-density lipoprotein receptor [LDLR] mutations and 4 with PCSK9 gain-of-function mutations) and 3 patients with heterozygous dominant-negative PCSK9 loss-of-function mutations were included in the preliminary study. Eight patients were enrolled in a second study assessing the effects of 2 g/day extended-release niacin. Apolipoprotein kinetics in VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), and Lp(a) were studied using stable isotope techniques. Plasma Lp(a) concentrations were increased in PCSK9-gain-of-function and familial hypercholesterolemia-LDLR groups compared with controls and PCSK9-loss-of-function groups (14±12 versus 5±4 mg/dL; P=0.04), but no change was observed in Lp(a) fractional catabolic rate. Subjects with PCSK9-loss-of-function mutations displayed reduced apoE (apolipoprotein E) concentrations associated with a VLDL-apoE absolute production rate reduction. Lp(a) and VLDL-apoE absolute production rates were correlated (r=0.50; P<0.05). ApoE-to-apolipoprotein (a) molar ratios in Lp(a) increased with plasma Lp(a) (r=0.96; P<0.001) but not with PCSK9 levels. Extended-release niacin-induced reductions in Lp(a) and VLDL-apoE absolute production rate were correlated (r=0.83; P=0.015). In contrast, PCSK9 reduction (-35%; P=0.008) was only correlated with that of VLDL-apoE absolute production rate (r=0.79; P=0.028). CONCLUSIONS: VLDL-apoE production could determine Lp(a) production and/or assembly. As PCSK9 inhibitors reduce plasma apoE and Lp(a) concentrations, apoE could be the link between PCSK9 and Lp(a).
OBJECTIVE: To clarify the association between PCSK9 (proprotein convertase subtilisin/kexin type 9) and Lp(a) (lipoprotein [a]), we studied Lp(a) kinetics in patients with loss-of-function and gain-of-function PCSK9 mutations and in patients in whom extended-release niacin reduced Lp(a) and PCSK9 concentrations. Approach and Results: Six healthy controls, 9 heterozygous patients with familial hypercholesterolemia (5 with low-density lipoprotein receptor [LDLR] mutations and 4 with PCSK9 gain-of-function mutations) and 3 patients with heterozygous dominant-negative PCSK9 loss-of-function mutations were included in the preliminary study. Eight patients were enrolled in a second study assessing the effects of 2 g/day extended-release niacin. Apolipoprotein kinetics in VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), and Lp(a) were studied using stable isotope techniques. Plasma Lp(a) concentrations were increased in PCSK9-gain-of-function and familial hypercholesterolemia-LDLR groups compared with controls and PCSK9-loss-of-function groups (14±12 versus 5±4 mg/dL; P=0.04), but no change was observed in Lp(a) fractional catabolic rate. Subjects with PCSK9-loss-of-function mutations displayed reduced apoE (apolipoprotein E) concentrations associated with a VLDL-apoE absolute production rate reduction. Lp(a) and VLDL-apoE absolute production rates were correlated (r=0.50; P<0.05). ApoE-to-apolipoprotein (a) molar ratios in Lp(a) increased with plasma Lp(a) (r=0.96; P<0.001) but not with PCSK9 levels. Extended-release niacin-induced reductions in Lp(a) and VLDL-apoE absolute production rate were correlated (r=0.83; P=0.015). In contrast, PCSK9 reduction (-35%; P=0.008) was only correlated with that of VLDL-apoE absolute production rate (r=0.79; P=0.028). CONCLUSIONS: VLDL-apoE production could determine Lp(a) production and/or assembly. As PCSK9 inhibitors reduce plasma apoE and Lp(a) concentrations, apoE could be the link between PCSK9 and Lp(a).
Entities:
Keywords:
apolipoprotein E; isotopes; kinetics; lipoprotein (a); loss of function mutation; niacin