VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly
Mikaël Croyal, Valentin Blanchard, Khadija Ouguerram, Maud Chétiveaux, Léa Cabioch, Thomas Moyon, Stéphanie Billon‐Crossouard, Audrey Aguesse, Karine Bernardeau, Cédric Le May, Laurent Flet, Gilles Lambert, Samy Hadjadj, Bertrand Cariou, Michel Krempf, Estelle Nobécourt-Dupuy
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).