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PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells
Open accessAbstract
PURPOSE OF REVIEW: Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to LDL receptor (LDLR) and targets it for lysosomal degradation in cells. Decreased hepatic clearance of plasma LDL-cholesterol is the primary gauge of PCSK9 activity in humans; however, PCSK9's evolutionary role may extend to other lipoprotein classes and processes. This review highlights studies that are providing novel insights into physiological regulation of PCSK9 transcription and plasma PCSK9 activity. RECENT FINDINGS: Recent studies indicate that circulating PCSK9 binds to apolipoprotein B100 on LDL particles, which in turn inhibits PCSK9's ability to bind to cell surface LDLRs. Negative feedback of secreted PCSK9 activity by LDL could serve to increase plasma excursion of triglyceride-rich lipoproteins and monitor lipoprotein remodeling. Recent findings have identified hepatocyte nuclear factor-1α as a key transcriptional regulator that cooperates with sterol regulatory element-binding protein-2 to control PCSK9 expression in hepatocytes in response to nutritional and hormonal inputs, as well as acute inflammation. SUMMARY: PCSK9 is an established target for cholesterol-lowering therapies. Further study of PCSK9 regulatory mechanisms may identify additional control points for pharmacological inhibition of PCSK9-mediated LDLR degradation. PCSK9 function could reflect ancient roles in the fasting-feeding cycle and in linking lipoprotein metabolism with innate immunity.
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![FIGURE 2 Model of proprotein convertase subtilisin/kexin type-9 dysregulation under conditions of elevated plasma proprotein convertase subtilisin/kexin type-9 concentration. At low concentrations of plasma PCSK9 (top panel), such as may be present in a low nutrient environment, PCSK9 senses the conversion of VLDL to LDL in the plasma compartment through its ability to bind to LDL. When plasma LDL is low relative to hepatic VLDL production and PCSK9 secretion, the majority of circulating PCSK9 is in a free active form and directs hepatic LDLR degradation. As the LDL/VLDL ratio increases, and as plasma PCSK9 levels decline in fasting, a progressively higher percentage of plasma PCSK9 becomes LDL-bound and inactive, thereby promoting hepatic clearance of LDL. At high concentrations of plasma PCSK9 and LDL (lower panel) PCSK9 activity is less sensitive to the VLDL-to-LDL conversion, and the regulatory pool of LDL-apoB100 is mainly a function of hepatic LDL clearance. Due to a relatively low binding affinity to LDL (Kd∼ 300 nM) [42▪▪], negative feedback control of PCSK9 activity becomes dysregulated at high PCSK9 levels. Although a higher percentage of total plasma PCSK9 may bind to LDL under conditions of hypercholesterolemia, because of increased hepatic PCSK9 secretion there remains a large component of free and active PCSK9 in the circulation.](/paper-figures/e68dcb06d8764ab9b349271b9680d6f7/pcsk9-and-ldlr-degradation-regulatory-mechanisms-in-circulation-and-in-cells-figure-2.jpg)
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“In the MK-0616 higher dose group (18 to 20 mg), LDL-C closely tracked with ApoB, supporting a shared mechanism of particle clearance through PCSK9 inhibition, consistent with its known effect on LDL receptor recycling [18].”
From Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials (2026) · cites this paper as [18]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“By inhibiting this interaction, PCSK9 targeted therapy preserves LDL receptor recycling, increases hepatic receptor abundance, and enhances clearance of circulating ApoB-containing lipoproteins [18].”
From Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials (2026) · cites this paper as [18]
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In the citing paper
“Mechanistically, PCSK9 binds hepatic LDL receptors and targets them for lysosomal degradation, thereby limiting receptor recycling and reducing hepatocyte surface receptor availability.”
From Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials (2026) · cites this paper as [18]
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In the citing paper
“By remaining bound to the LDLR, PCSK9 prevents the conformational change of the LDLR that is required for its recycling back to the plasma membrane, therefore, inhibiting this recycling [38]. Instead, the PCSK9–LDLR complex is directed to the lysosome where both proteins are degraded (Figure 1C), thereby reducing the amount of LDLR in the cell [39].”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [39]
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In the citing paper
“Proprotein convertase subtilisin/kexin type 9 and the asialoglycoprotein receptor 1 both independently interact with the LDLR and direct it towards the lysosome for degradation.”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [39]
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In the citing paper
“As PCSK9 reroutes internalized LDLR for intracellular degradation (Lagace, 2014)”
From γ-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor (2018) · cites this paper as Lagace, 2014
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In the citing paper
“PCSK9 plays an important role in cholesterol homeostasis as a result of its ability to reduce cell-surface LDLR levels7.”
From Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA (2018) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“Post-translational regulation of LDLR is primarily governed by PCSK9 that upon binding to cell-surface LDLR mediates its degradation7.”
From Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA (2018) · cites this paper as [7]
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In the citing paper
“PCSK9 is another potent LDLR degrader aside from IDOL (28, 29).”
From SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1 (2021) · cites this paper as [29]
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Citations
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Metadata
- Authors
- Lagace, T. A.
- Affiliations
- Ottawa Heart Institute (CA)
- Corresponding author
- Lagace, Thomas A.
- ORCID
- Lagace, Thomas A.
- Venue
- Current Opinion in Lipidology
- Published
- 2014-10
- Volume
- 25
- Issue
- 5
- Pages
- 387-393
- ISSN
- 0957-9672 (ISSN-L)
- PMC
- PMC4166010
- OpenAlex
- W2036304437
- Cited by
- 372
- References
- 7
- Citations by year
- 2026: 28 · 2025: 41 · 2024: 55 · 2023: 37 · 2022: 38 · 2021: 36 · 2020: 36 · 2019: 25 · 2018: 25 · 2017: 20 · 2016: 18 · 2015: 13
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Current Opinion in Lipidology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- Canadian Institutes of Health Research (106462_1)
- 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, LDL receptor, LDLR degradation, lysosomal degradation, apolipoprotein B-100, triglyceride-rich lipoproteins, lipoprotein remodeling, HNF1A, SREBP2, PCSK9 inhibitors, innate immunity, lipoprotein metabolism
- MeSH terms
- Proprotein Convertase 9, Apolipoproteins B, Gene Expression Regulation, Humans, Immunity, Innate, Inflammation, Lipoproteins, LDL, Lysosomes, Protein Binding, Receptors, LDL, Serine Endopeptidases, Hepatocytes, Proprotein Convertases, Proteolysis
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