VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly. Issue 3 (March 2020)

• Record Type: Journal Article
• Authors: Croyal, Mikaël; Blanchard, Valentin; Ouguerram, Khadija; Chétiveaux, Maud; Cabioch, Léa; Moyon, Thomas; Billon-Crossouard, Stéphanie; Aguesse, Audrey; Bernardeau, Karine; Le May, Cédric; Flet, Laurent; Lambert, Gilles; Hadjadj, Samy; Cariou, Bertrand; Krempf, Michel; Nobécourt-Dupuy, Estelle
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 40:Issue 3(2020)
• Publication Date: 2020-03
• Subjects: apolipoprotein E -- isotopes -- kinetics -- lipoprotein (a) -- loss of function mutation -- niacin; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.119.313877
• Languages: English
• ISSNs: 1079-5642

Abstract

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). Abstract : Supplemental Digital Content is available in the text.