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  • Title: VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly.
    Author: Croyal M, Blanchard V, Ouguerram K, Chétiveaux M, Cabioch L, Moyon T, Billon-Crossouard S, Aguesse A, Bernardeau K, Le May C, Flet L, Lambert G, Hadjadj S, Cariou B, Krempf M, Nobécourt-Dupuy E.
    Journal: Arterioscler Thromb Vasc Biol; 2020 Mar; 40(3):819-829. PubMed ID: 32078365.
    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).
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