ArticleJournal of the American College of Cardiology2021
Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies.
Article in Journal of the American College of Cardiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
15 citing papers in PubMed, 30 citations in OpenAlex.
- Evolocumab for prevention of microvascular dysfunction in patients undergoing percutaneous coronary intervention: the randomised, open-label EVOCATION trial.EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology · 2022Trial
- Dyslipidaemia and hepatic steatosis: mechanisms and implications for lipid-lowering therapy.Nature reviews. Cardiology · 2026Review
- PROTAC-mediated PCSK9 degradation attenuates atherosclerosis and improves plaque composition via suppression of NF-κB/TNF-α pathway.BMC medicine · 2026Article
- Review
- LDL-Bound PCSK9 Has a Slower Clearance Kinetic and Higher Use for HSPGs Than Free-PCSK9-Brief Report.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- PCSK9 deficiency promotes the development of peripheral neuropathy.JCI insight · 2025Article
- Impact of In-Hospital PCSK9 Inhibition on Myocardial Inflammation After Myocardial Infarction: A Randomized Clinical Trial.JACC. Basic to translational science · 2025Article
- Engineered extracellular vesicles as nanosponges for lysosomal degradation of PCSK9.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Proprotein convertase subtilisin/kexin 9 inhibitor downregulates microRNA-130a-3p expression in hepatocytes to alleviates atherosclerosis progression.Naunyn-Schmiedeberg's archives of pharmacology · 2024Article
- High interindividual variability in LDL-cholesterol reductions after inclisiran administration in a real-world multicenter setting in Germany.Clinical research in cardiology : official journal of the German Cardiac Society · 2023Article
- Updates in Small Interfering RNA for the Treatment of Dyslipidemias.Current atherosclerosis reports · 2023Review
- Synthetic Site-Specific Antibody-Ligand Conjugates Promote Asialoglycoprotein Receptor-Mediated Degradation of Extracellular Human PCSK9.ACS chemical biology · 2023Article
- PCSK9 Monoclonal Antibodies: New Developments and Their Relevance in a Nucleic Acid-Based Therapy Era.Current atherosclerosis reports · 2022Review
- NAFLD fibrosis score is correlated with PCSK9 and improves outcome prediction of PCSK9 in patients with chest pain: a cohort study.Lipids in health and disease · 2022Article
- Effect of Statins and PCSK9 Inhibition on Metabolic Dysfunction-Associated Steatotic Liver Disease.Journal of digestive diseasesReview
Corrections and comments
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundMonoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9i) lower LDL-C by up to 60% and increase plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels by 10-fold.
objectivesThe authors studied the reasons behind the robust increase in plasma PCSK9 levels by testing the hypothesis that mechanisms beyond clearance via the low-density lipoprotein receptor (LDLR) contribute to the regulation of cholesterol homeostasis.
methodsIn clinical cohorts, animal models, and cell-based studies, we measured kinetic changes in PCSK9 production and clearance in response to PCSK9i.
resultsIn a patient cohort receiving PCSK9i therapy, plasma PCSK9 levels rose 11-fold during the first 3 months and then plateaued for 15 months. In a cohort of healthy volunteers, a single injection of PCSK9i increased plasma PCSK9 levels within 12 hours; the rise continued for 9 days until it plateaued at 10-fold above baseline. We recapitulated the rapid rise in PCSK9 levels in a mouse model, but only in the presence of LDLR. In vivo turnover and in vitro pulse-chase studies identified 2 mechanisms contributing to the rapid increase in plasma PCSK9 levels in response to PCSK9i: 1) the expected delayed clearance of the antibody-bound PCSK9; and 2) the unexpected post-translational increase in PCSK9 secretion.
conclusionsPCSK9 re-entry to the liver via LDLR triggers a sensing loop regulating PCSK9 secretion. PCSK9i therapy enhances the secretion of PCSK9, an effect that contributes to the increased plasma PCSK9 levels in treated subjects.
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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.