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

Arterioscler Thromb Vasc Biol. 2020 Mar;40(3):819-829. doi: 10.1161/ATVBAHA.119.313877. Epub 2020 Feb 6.


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).

Keywords: apolipoprotein E; isotopes; kinetics; lipoprotein (a); loss of function mutation; niacin.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anticholesteremic Agents / therapeutic use
  • Apolipoproteins E / blood*
  • Biomarkers / blood
  • Case-Control Studies
  • Delayed-Action Preparations
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Hyperlipoproteinemia Type II / blood*
  • Hyperlipoproteinemia Type II / diagnosis
  • Hyperlipoproteinemia Type II / drug therapy
  • Hyperlipoproteinemia Type II / genetics
  • Kinetics
  • Lipoprotein(a) / biosynthesis
  • Lipoprotein(a) / blood*
  • Lipoproteins, VLDL / blood*
  • Male
  • Middle Aged
  • Mutation
  • Niacin / therapeutic use
  • Phenotype
  • Proprotein Convertase 9 / genetics
  • Randomized Controlled Trials as Topic
  • Receptors, LDL / genetics
  • Treatment Outcome
  • Young Adult


  • Anticholesteremic Agents
  • ApoE protein, human
  • Apolipoproteins E
  • Biomarkers
  • Delayed-Action Preparations
  • LDLR protein, human
  • Lipoprotein(a)
  • Lipoproteins, VLDL
  • Receptors, LDL
  • Niacin
  • PCSK9 protein, human
  • Proprotein Convertase 9