Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies

Carlota Oleaga, Michael D. Shapiro, Joshua Hay, Paul A. Mueller, Joshua Miles, Cecilia Huang, Emily Friz, Hagai Tavori, Peter P. Toth, Cezary Wójcik, Bruce A. Warden, Jonathan Q. Purnell, P. Barton Duell, Nathalie Pamir, Sergio Fazio

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1437-1449
Number of pages13
JournalJournal of the American College of Cardiology
Volume78
Issue number14
DOIs
StatePublished - Oct 5 2021
Externally publishedYes

Keywords

  • LDL cholesterol
  • LDL receptor
  • PCSK9
  • cholesterol homeostasis
  • monoclonal antibodies
  • turnover studies

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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