ArticleJournal of lipid research2014
Internalized PCSK9 dissociates from recycling LDL receptors in PCSK9-resistant SV-589 fibroblasts.
Article in Journal of lipid research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 32 citations in OpenAlex.
- PCSK9-promoted LDLR degradation: Recruitment or prevention of essential cofactors?Metabolism open · 2025Article
- Role of PCSK9 inhibition during the inflammatory stage of SARS-COV-2: an updated review.Annals of medicine and surgery (2012) · 2024Review
- Soluble PCSK9 Inhibition: Indications, Clinical Impact, New Molecular Insights and Practical Approach-Where Do We Stand?Journal of clinical medicine · 2023Review
- Proprotein Convertase Subtilisin/Kexin 9 as a Modifier of Lipid Metabolism in Atherosclerosis.Biomedicines · 2023Review
- Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding.Frontiers in physiology · 2022Article
- Development of a Novel DNA Oligonucleotide Targeting Low-Density Lipoprotein Receptor.Molecular therapy. Nucleic acids · 2020Article
- A transient amphipathic helix in the prodomain of PCSK9 facilitates binding to low-density lipoprotein particles.The Journal of biological chemistry · 2020Article
- Cell-associated heparin-like molecules modulate the ability of LDL to regulate PCSK9 uptake.Journal of lipid research · 2019Article
- Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis.Molecular medicine reports · 2017Article
- Trafficking Dynamics of PCSK9-Induced LDLR Degradation: Focus on Human PCSK9 Mutations and C-Terminal Domain.PloS one · 2016Article
- Hypercholesterolemia, low density lipoprotein receptor and proprotein convertase subtilisin/kexin-type 9.Journal of biomedical research · 2015Review
- On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects.Atherosclerosis · 2015Review
- PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE.Journal of lipid research · 2014Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Secreted PCSK9 binds to cell surface LDL receptor (LDLR) and directs the receptor for lysosomal degradation. PCSK9 is potent at inducing LDLR degradation in cultured liver-derived cells, but it is considerably less active in immortalized fibroblasts. We examined PCSK9 trafficking in SV-589 human skin fibroblasts incubated with purified recombinant wild-type PCSK9 or gain-of-function mutant PCSK9-D374Y with increased LDLR binding affinity. Despite LDLR-dependent PCSK9 uptake, cell surface LDLR levels in SV-589 fibroblasts were only modestly reduced by wild-type PCSK9, even at high nonphysiological concentrations (20 µg/ml). Internalized (125)I-labeled wild-type PCSK9 underwent lysosomal degradation at high levels, indicating its dissociation from recycling LDLRs. PCSK9-D374Y (2 µg/ml) reduced cell surface LDLRs by approximately 50%, but this effect was still blunted compared with HepG2 hepatoma cells. Radioiodinated PCSK9-D374Y was degraded less efficiently in SV-589 fibroblasts, and Alexa488-labeled PCSK9-D374Y trafficked to both lysosomes and endocytic recycling compartments. Endocytic recycling assays showed that more than 50% of internalized PCSK9-D374Y recycled to the cell surface compared with less than 10% for wild-type PCSK9. These data support that wild-type PCSK9 readily dissociates from the LDLR within early endosomes of SV-589 fibroblasts, contributing to PCSK9-resistance. Although a large proportion of gain-of-function PCSK9-D374Y remains bound to LDLR in these cells, degradative activity is still diminished.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.