VLDL-apoE production may drive Lp(a) synthesis, a kinetic study of PCSK9 mutation carriers and niacin-treated patients (Arterioscler Thromb Vasc Biol 2020)

Original title: VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly

Arterioscler Thromb Vasc Biol · 6 February 2020 · 7

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 et al.

Using stable isotope kinetic techniques, researchers studied Lp(a), VLDL and LDL apolipoprotein turnover in 6 healthy controls, 9 heterozygous familial hypercholesterolaemia patients (5 with LDLR mutations, 4 with PCSK9 gain-of-function mutations), 3 patients with PCSK9 loss-of-function mutations, and 8 patients treated with 2 g/day extended-release niacin. Plasma Lp(a) was higher in the PCSK9 gain-of-function and LDLR groups than in loss-of-function patients (14±12 vs 5±4 mg/dL, P=0.04). ApoE-to-apo(a) molar ratios in Lp(a) correlated with plasma Lp(a) (r=0.96, P<0.001), and niacin-induced reductions in Lp(a) correlated with reductions in VLDL-apoE production rate (r=0.83, P=0.015), while niacin’s PCSK9 reduction (-35%, P=0.008) correlated only with VLDL-apoE production (r=0.79, P=0.028). The findings suggest VLDL-apoE production determines Lp(a) synthesis or assembly, positioning apoE as a mechanistic link between PCSK9 and Lp(a).

Original 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).

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.