Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders

Abstract

Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in carriers of mutations in LCAT, ABCA1, or APOAI genes, and lipoprotein distribution was analyzed by FPLC. Carriers of one or two mutations in the LCAT gene show plasma PCSK9 levels comparable to that of unaffected family controls (homozygotes, 159.4 ng/mL (124.9;243.3); heterozygotes, 180.3 ng/mL (127.6;251.5) and controls, 190.4 ng/mL (146.7;264.4); P for trend = 0.33). Measurement of PCSK9 in plasma of subjects carrying mutations in ABCA1 or APOAI genes confirmed normal values. When fractionated by FPLC, PCSK9 peaked in a region between LDL and HDL in control subjects. In carriers of all HDL defects, lipoprotein profile shows a strong reduction of HDL, but the distribution of PCSK9 was superimposable to that of controls. In conclusion, the present study demonstrates that in genetically determined low HDL states plasma PCSK9 concentrations and lipoprotein distribution are preserved, thus suggesting that HDL may not be involved in PCSK9 transport in plasma.

Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer’s Disease

“…Interestingly, CSF samples extracted from AD patients have lower ex-vivo capacity to promote ABCA1-mediated cholesterol efflux compared to controls (Yassine et al, 2016). Finally, a further level of complexity could be the possible binding between PCSK9 and apoE-containing lipoproteins as previously described for LDL (Tavori et al, 2013), Lipoprotein (a) (Tavori et al, 2016) and HDL (Ferri et al, 2016a; Ruscica et al, 2018).…”

Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9

“…The minimum detectable PCSK9 concentration was 0.219 ng/mL. 23 Concerning the evaluation of PCSK9 in the conditioned medium, HepG2 cells were cultured in 12-well plates (6 Â 10 5 cells/well). The medium (200 mL) was collected after 24-hour treatment with leptin, resistin, and simvastatin.…”

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

“…However, since only 1 out of 175 Lp(a) particles binds to PCSK9, this would represent a very small percentage of total Lp(a) that is complexed [ 80 ]. Moreover, a study by our group showed that, irrespective of the presence of Lp(a), the analysis of PCSK9 lipoprotein distribution by Fast Protein Liquid Chromatography (FPLC) is not affected [ 81 ].…”