Journal
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Volume 78, Issue 14, Pages 1437-1449Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2021.07.056
Keywords
cholesterol homeostasis; LDL cholesterol; LDL receptor; monoclonal antibodies; PCSK9; turnover studies
Categories
Funding
- National Institutes of Health [5RO1HL132985]
- Retrophin/Travere
- Regeneron
- Regenxbio
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This study investigated the mechanisms behind the increase in plasma PCSK9 levels in response to PCSK9i therapy. The findings suggest that PCSK9i enhances PCSK9 secretion, contributing to the elevated plasma PCSK9 levels in treated subjects.
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. (J Am Coll Cardiol 2021;78:1437-1449) (c) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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