Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies
| Autor: | Joshua Hay, Peter P. Toth, Carlota Oleaga, Joshua Miles, Nathalie Pamir, Jonathan Q. Purnell, Emily Friz, Cecilia Huang, Sergio Fazio, Paul Mueller, Michael D. Shapiro, P. Barton Duell, Bruce A. Warden, Cezary Wojcik, Hagai Tavori |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Adult
Male endocrine system animal structures medicine.drug_class Hypercholesterolemia Monoclonal antibody Article cholesterol homeostasis PCSK9 Animals Humans Medicine Secretion Aged Retrospective Studies Mice Knockout business.industry PCSK9 Inhibitors fungi Subtilisin Antibodies Monoclonal LDL receptor Cholesterol LDL Middle Aged Lipid Metabolism Proprotein convertase Inhibitory antibodies Molecular biology Healthy Volunteers turnover studies enzymes and coenzymes (carbohydrates) HEK293 Cells Liver Receptors LDL LDL cholesterol biological sciences Kexin Female monoclonal antibodies Proprotein Convertases Proprotein Convertase 9 Cardiology and Cardiovascular Medicine business |
| Zdroj: | Journal of the American College of Cardiology |
| ISSN: | 0735-1097 |
| DOI: | 10.1016/j.jacc.2021.07.056 |
| Popis: | BACKGROUND Monoclonal 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. OBJECTIVES The 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. METHODS In clinical cohorts, animal models, and cell-based studies, we measured kinetic changes in PCSK9 production and clearance in response to PCSK9i. RESULTS In 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. CONCLUSIONS PCSK9 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. |
| Databáze: | OpenAIRE |
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