Hepatic Sensing Loop Regulates PCSK9 Secretion in Response to Inhibitory Antibodies

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.

PCSK9 Monoclonal Antibodies: New Developments and Their Relevance in a Nucleic Acid–Based Therapy Era

“…Of note, it has been recently shown that treatment with the PCSK9-mAb alirocumab attenuated alcohol-induced steatohepatitis in a rat model [ 55 ]. Interestingly, while PCSK9-mAb decrease free-circulating PCSK9 [ 56 – 58 ], the levels of total plasma PCSK9 are increased [ 56 , 59 – 61 ], most likely reflecting the longer half-life of the inactive PCSK9-mAb:PCSK9 complex [ 56 , 59 ] and possibly also the compensatory increase in hepatic PCSK9 production [ 62 ].…”

NAFLD fibrosis score is correlated with PCSK9 and improves outcome prediction of PCSK9 in patients with chest pain: a cohort study

“…It is known that PCSK9 is mainly secreted by liver cells and is involved in lipid metabolism [ 27 ]. Moreover, a recent study found that hepatic reentry of plasma PCSK9 triggered the sensing loop regulating PCSK9 and low-density lipoprotein secretion [ 28 ], suggesting that liver dysfunction could change the circulating PCSK9 concentration and influence its function. Whether liver damage, especially liver fibrosis, has an impact on the predictive ability of PCSK9 for adverse cardiovascular outcomes is worth exploring.…”

Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9

“…At this time point, the percentage decrease in LDL-C was approximately 50 % after 15 days, associated to a significant reduction of ApoB and non-HDL-C. Interestingly, in patients under chronic treatment with both evolocumab and alirocumab a massive increase (3 ÷ 7 fold) of total PCSK9 plasma levels has been reported [55]. This effect is due to the reduced clearance of PCSK9 bound to mAbs by the liver through the LDLR and by an unexpected, and still debated, post-translational increase in PCSK9 secretion [56].…”