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

Abstract

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-lowdensity 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).

APOE gene variants in primary dyslipidemia

“…Classical knowledge is that LDL does not have apoE, nevertheless, since apoE binds to lipids through its C-terminal domain it seems difficult that it binds to HDL, VLDL, IDL and Lp(a) but not LDL at all. Indeed, lipoproteins isolated by flotation sequential ultracentrifugation showed that apoE represents 0.40%, 0.10% and 0.38% of the total mass of VLDL, LDL and HDL, respectively [2], and is found in HDL (61 ± 27%), VLDL (35 ± 25%), Lp(a) (4 ± 9%) and LDL (1 ± 1%) in fasting plasma [3]. Lipoproteins isolated by anti-apoE immunoaffinity chromatography showed the presence of 21, 19, and 5 molecules of apoE in a portion of VLDL, HDL, and LDL respectively [4].…”

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

“…They range from a key role of the LDLR in Lp(a) catabolism to a reduced Lp(a) synthesis. Recently, a further mechanism has been hypothesized, i.e., Very-Low-Density Lipoprotein (VLDL)–apoE production could influence Lp(a) production and/or assembly [ 69 ]. Epidemiological studies have shown differences in plasma Lp(a) concentrations between apoE genotypes based on the three major E isoforms (ε2/ε3/ε4) [ 70 ].…”

Relation of Serum Lipoprotein(a) Levels to Lipoprotein and Apolipoprotein Profiles and Atherosclerotic Diseases in Japanese Patients with Heterozygous Familial Hypercholesterolemia: Familial Hypercholesterolemia Expert Forum (FAME) Study

“…The median Lp(a) in this study of 20.8 mg/dL seems to be higher than reported in previous studies on Japanese FH patients (12.1 mg/dL) and Japanese healthy The values are expressed according to Lp(a) categories at baseline in heterozygous FH patients under medical treatment. 25) , although exact mechanisms explaining the relationship remain to be uncovered.…”