Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies.
J Am Coll Cardiol
; 78(14): 1437-1449, 2021 10 05.
Article
em En
| MEDLINE
| ID: mdl-34593126
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Pró-Proteína Convertase 9
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Inibidores de PCSK9
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Fígado
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Anticorpos Monoclonais
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article