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. 2019 Jan;60(1):161-167.
doi: 10.1194/jlr.P088583. Epub 2018 Oct 15.

The interrelations between PCSK9 metabolism and cholesterol synthesis and absorption

Günther Silbernagel  1   2 , Lars K Steiner  3 , Tim Hollstein  2 , Günter Fauler  4 , Hubert Scharnagl  4 , Tatjana Stojakovic  4 , Friederike Schumann  2 , Bediha Bölükbasi  5 , Winfried März  4   6   7 , Elisabeth Steinhagen-Thiessen  2 , Ulrich Laufs  8 , Ursula Kassner  2
Affiliations
Free PMC article

The interrelations between PCSK9 metabolism and cholesterol synthesis and absorption

Günther Silbernagel et al. J Lipid Res. 2019 Jan.
Free PMC article

Abstract

Very few studies have investigated the interrelations between proprotein convertase subtilisin/kexin type 9 (PCSK9) metabolism, cholesterol synthesis, and cholesterol absorption. We aimed to address this issue in a large clinical trial of 245 patients with hypercholesterolemia. Serum lipids, PCSK9, lathosterol (cholesterol synthesis marker), campesterol, and sitosterol (cholesterol absorption markers) were measured before and 4-8 weeks after the start of treatment with PCSK9-antibodies (alirocumab or evolocumab). The patients had mean (standard error) LDL-cholesterol and PCSK9 concentrations of 3.87 (0.10) mmol/l and 356 (17) ng/ml, respectively. Eighty-four patients received no lipid-lowering pretreatment, 26 ezetimibe, 38 statins, and 97 ezetimibe + statins. Circulating PCSK9 increased in parallel with the potency of lipid-lowering pretreatment with circulating PCSK9 being highest in the ezetimibe + statin group (P < 0.001). Treatment with PCSK9-antibodies strongly decreased LDL-cholesterol, lathosterol, campesterol, and sitosterol (all P < 0.001) but hardly affected noncholesterol sterol to cholesterol ratios. Lipid-lowering pretreatment was not associated with the effects of PCSK9-antibodies on noncholesterol sterols (all P > 0.05). Summing up, circulating PCSK9 is increased by cholesterol synthesis and absorption inhibitors. Increased PCSK9 expression may partly explain the strong reductions of LDL-cholesterol achieved with PCSK9-antibodies after such pretreatment. On the other hand, treatment with PCSK9-antibodies does not significantly change the balance between cholesterol synthesis and absorption.

Keywords: cholesterol metabolism; cholesterol/absorption; cholesterol/biosynthesis; clinical trials; low density lipoprotein; proprotein convertase subtilisin/kexin type 9.

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Conflict of interest statement

G.S. reports grants and personal fees from Sanofi, grants and nonfinancial support from Amgen, nonfinancial support from Bayer, and grants from Numares outside the submitted work. T.H. reports travel fees from Sanofi and Amgen. W.M. reports other from Synlab Services GmbH, other from Synlab Holding GmbH, grants and personal fees from Siemens Diagnostics, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from Amgen, grants and personal fees from AstraZeneca, grants and personal fees from Danone Research, grants and personal fees from Sanofi, personal fees from Roche, personal fees from Merck Sharp & Dohme, grants and personal fees from Pfizer, personal fees from Synageva, grants and personal fees from BASF, grants from Abbott Diagnostics, and grants and personal fees from Numares outside the submitted work. U.L. reports personal fees from Amgen and Sanofi. U.K. reports personal fees from Fresenius Medical Care, Sanofi, Alexion, Berlin Chemie, Amgen, and Synlab Holding GmBH outside of the submitted work. L.K.S., G.F., H.S., T.S., F.S., B.B., and E.S-T. have nothing to disclose.

Figures

Fig. 1.
Fig. 1.
Receptor-mediated uptake of LDL from the blood stream into the liver without (A) and with (B) PCSK9-antibody treatment. (This figure was composed using free medical images obtained from https://smart.servier.com.)
See this image and copyright information in PMC

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