Beyond LDL-C lowering: Distinct molecular sphingolipids are good indicators of proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency

被引：36

作者：

Janis, Minna T. ^{[1
]}

Tarasov, Kirill ^{[1
]}

Ta, Hung Xuan ^{[1
]}

Suoniemi, Matti ^{[1
]}

Ekroos, Kim ^{[1
]}

Hurme, Reini ^{[1
]}

Lehtimaki, Terho ^{[2
,3
]}

Paiva, Hannu ^{[3
,4
]}

Kleber, Marcus E. ^{[6
,7
]}

Maerz, Winfried ^{[7
,8
,9
]}

Prat, Annik ^{[10
]}

Seidah, Nabil G. ^{[10
]}

Laaksonen, Reijo ^{[1
,3
,5
]}

机构：

[1] Zora Biosci, FI-02150 Espoo, Finland

[2] Univ Tampere, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland

[3] Tampere Univ Hosp, Tampere, Finland

[4] Univ Tampere, Dept Internal Med, FIN-33101 Tampere, Finland

[5] Univ Tampere, Dept Sci Ctr, FIN-33101 Tampere, Finland

[6] Lur Study Nonprofit LLC, Freiburg, Germany

[7] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth, Heidelberg, Germany

[8] Synlab Acad, Mannheim, Germany

[9] Med Univ Graz, Clin Inst Med & Clin Lab Diagnost, Graz, Austria

[10] Clin Res Inst Montreal, Montreal, PQ H2W 1R7, Canada

来源：

ATHEROSCLEROSIS | 2013年 / 228卷 / 02期

关键词：

PCSK9; Biomarker; Lipidomics; HIGH-THROUGHPUT; CHOLESTEROL;

D O I：

10.1016/j.atherosclerosis.2013.03.029

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objectives: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been proposed to be a potential new therapeutic target for treatment of hypercholesterolaemia. However, little is known about the effects of PCSK9 inhibition on the lipidome. Methods: We performed molecular lipidomic analyses of plasma samples obtained from PCSK9-deficient mice, and serum of human carriers of a loss-of-function variant in the PCSK9 gene (R46L). Results: In both mouse and man, PCSK9 deficiency caused a decrease in several cholesteryl esters (CE) and short fatty acid chain containing sphingolipid species such as CE 16: 0, glucosyl/galactosylceramide (Glc/GalCer) d18:1/16:0, and lactosylceramide (LacCer) d18:1/16:0. In mice, the changes in lipid concentrations were most prominent when animals were given regular chow diet. In man, a number of molecular lipid species was shown to decrease significantly even when LDL-cholesterol was non-significantly reduced by 10% only. Western diet attenuated the lipid lowering potency of PCSK9 deficiency in mice. Conclusions: Plasma molecular lipid species may be utilized for characterizing novel compounds inhibiting PCSK9 and as sensitive efficacy markers of the PCSK9 inhibition. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

引用

页码：380 / 385

页数：6

共 23 条

[1] Mutations in PCSK9 cause autosomal dominant hypercholesterolemia [J].