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Cited by 86Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismLipid metabolism and disorders

On the function and homeostasis of PCSK9: Reciprocal interaction with LDLR and additional lipid effects

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Tavori, Hagai, Rashid, Shirya, Fazio, Sergio·2015·Atherosclerosis
DOI 10.1016/j.atherosclerosis.2014.12.017PMC PMC4562333
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Abstract

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulatory ligand that terminates the lifecycle of the low-density lipoprotein (LDL) receptor (LDLR) thus affecting plasma LDL-cholesterol (LDL-C) levels. Recent evidence shows that in addition to the straightforward mechanism of action, there are more complex interactions between PCSK9, LDLR and plasma lipoprotein levels, including: (a) the presence of both parallel and reciprocal regulation of surface LDLR and plasma PCSK9; (b) a correlation between PCSK9 and LDL-C levels dependent not only on the fact that PCSK9 removes hepatic LDLR, but also due to the fact that up to 40% of plasma PCSK9 is physically associated with LDL; and (c) an association between plasma PCSK9 production and the assembly and secretion of triglyceride-rich lipoproteins. The effect of PCSK9 on LDLR is being successfully utilized toward the development of anti-PCSK9 therapies to reduce plasma LDL-C levels. Current biochemical research has uncovered additional mechanisms of action and interacting partners for PCSK9, and this opens the way for a more thorough understanding of the regulation, metabolism, and effects of this interesting protein.

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  • Clearance of circulating PCSK9 is largely mediated by LDLR-dependent uptake.

    “As the clearance of circulating PCSK9 is largely mediated by LDLR-dependent uptake 25 , higher plasma PCSK9 in RalGAPB HKO mice is probably due to reduced LDLR-mediated clearance, not increased PCSK9 production.”

    From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [25]

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Authors
Tavori, H., Rashid, S., & Fazio, S.
Affiliations
  • Oregon Health & Science University (US)
  • Dalhousie University (CA)
Corresponding author
Fazio, Sergio
ORCID
Venue
Atherosclerosis
Publisher
Elsevier BV
Published
2015-02
Volume
238
Issue
2
Pages
264-270
ISSN
0021-9150 (ISSN-L)
DOI
10.1016/j.atherosclerosis.2014.12.017
PMC
PMC4562333
OpenAlex
W2086048382
Cited by
86
References
6
Citations by year
2026: 9 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 9 · 2021: 7 · 2020: 4 · 2019: 7 · 2018: 4 · 2017: 11 · 2016: 11 · 2015: 10
FWCI
1.98
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Atherosclerosis (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (R01-HL106845)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
PCSK9, LDL receptor, LDL cholesterol, triglyceride-rich lipoproteins, lipoprotein metabolism, cholesterol homeostasis
MeSH terms
Proprotein Convertase 9, Animals, Hypolipidemic Agents, Enzyme Inhibitors, Homeostasis, Humans, Cholesterol, LDL, Protein Binding, Receptors, LDL, Serine Endopeptidases, Triglycerides, Proprotein Convertases, Dyslipidemias, Lipid Metabolism, Molecular Targeted Therapy

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