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Beyond LDL-C lowering: Distinct molecular sphingolipids are good indicators of proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency
Open accessAbstract
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.
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PCSK9 inactivation alters the levels of several other circulating lipid classes and species.
“In addition, PCSK9 inactivation alters the levels of several other circulating lipid classes and species.”
From PCSK9 deficiency alters brain lipid composition without affecting brain development and function (2023) · cites this paper as Jänis et al., 2013
PCSK9 affects peripheral lipids beyond cholesterol and plays a key role in systemic lipid metabolism.
“Several studies have reported that PCSK9 affects peripheral lipids beyond cholesterol and hence plays a key role in systemic lipid metabolism (Jänis et al., 2013; Hilvo et al., 2018).”
From PCSK9 deficiency alters brain lipid composition without affecting brain development and function (2023) · cites this paper as Jänis et al., 2013
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PCSK9 deficiency alters brain lipid composition without affecting brain development and function
Pärn, A., Olsen, D., Tuvikene, J., Kaas, M., Borisova, E., Bilgin, M., Elhauge, M., Vilstrup, J., Madsen, P., Ambrozkiewicz, M. C., et al. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1084633 · Cited by 16
Metadata
- Authors
- Jänis, M. T., Tarasov, K., Ta, H. X., Suoniemi, M., Ekroos, K., Hurme, R., Lehtimäki, T., Päivä, H., Kleber, M. E., März, W., Prat, A., Seidah, N. G., & Laaksonen, R.
- Affiliations
- Zora Biosciences (Finland) (FI)
- Tampere University Hospital (FI)
- Heidelberg University (DE)
- Medical University of Graz (AT)
- Montreal Clinical Research Institute (CA)
- Corresponding author
- Laaksonen, Reijo
- ORCID
- Venue
- Atherosclerosis
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 228
- Issue
- 2
- Pages
- 380-385
- ISSN
- 0021-9150 (ISSN-L)
- OpenAlex
- W2024624676
- Cited by
- 41
- References
- 2
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 3 · 2014: 3 · 2013: 2
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Atherosclerosis (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Finnish Funding Agency for Technology and Innovation
- TEKES and the European Community's Seventh Framework Programme (201668)
- CIHR (MOP 102741, CTP 82946)
- Canada chair (216684)
- Competitive Research Funding of the Tampere University Hospital (9M048, 9N035)
- Emil Aaltonen Foundation
- Finnish Foundation for Cardiovascular Research
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- PCSK9 inhibition, sphingolipids, lipidomics, cholesterol esters, glucosylceramide, galactosylceramide, lactosylceramide, hypercholesterolemia, Western diet, LDL cholesterol
- MeSH terms
- Proprotein Convertase 9, Animals, Cholesterol Esters, Genotype, Humans, Cholesterol, LDL, Male, Mutation, Phenotype, Prospective Studies, Serine Endopeptidases, Sphingolipids, Biomarkers, Mice, Knockout, Proprotein Convertases, Mice
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