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

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).

• Authors: 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
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 40 Issue 3 Pg. 819-829 (03 2020) ISSN: 1524-4636 [Electronic] United States
• PMID: 32078365 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, diagnosis, drug therapy, genetics)
• Kinetics
• Lipoprotein(a) (biosynthesis, 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