LDL-Bound PCSK9 Has a Slower Clearance Kinetic and Higher Use for HSPGs Than Free-PCSK9.

Abstract

Background: Hepatic heparan sulfate proteoglycans (HSPGs) accelerate the clearance of PCSK9 (proprotein convertase subtilisin/kexin type 9). We tested the hypothesis that free- and LDL (low-density lipoprotein)-bound PCSK9 forms have different HSPG-mediated clearance kinetics.

Methods: Metabolic and turnover studies were performed after administration of free- and LDL-bound PCSK9 to 2 HSPG knockout mouse models: (1) Global knockout of syndecan-1 (Sdc1^-/-), an HSPG involved in hepatic triglyceride clearance; and (2) hepatocyte-specific knockout of heparan sulfate N-deacetylase/N-sulfotransferase (AlbCre⁺Ndst1^f/f).

Results: The clearance of both free- and LDL-bound PCSK9 followed a 2-phase decay behavior comprising a fast and a slow phase. The more notorious effect of HSPG deletion was on the slow phase: the clearance of free-PCSK9 was faster in Sdc1^-/- mice (t_1/2,slow 13.5±1.5 minutes; P=0.0305) than in wild-type (t_1/2,slow 28.8±4.2 minutes) and AlbCre⁺Ndst1^f/f mice (t_1/2,slow 32.7±4.9 minutes). The clearance of LDL-bound PCSK9 was slower yet not statistically significant in Sdc1^-/- mice (t_1/2,slow 111.2±21.6 minutes) than in wild-type (t_1/2,slow 52±6.4 minutes) and AlbCre⁺Ndst1^f/f mice (t_1/2,slow 39.55±2.96 minutes). However, the area under the curve showed a delayed clearance of LDL-bound PCSK9 in Sdc1^-/- mice (44 576±2435 min×ng, P=0.004) but not in AlbCre⁺Ndst1^f/f (34 738±3721 min×ng, P=0.578) mice compared with wild-type (30 865±1907 min×ng). Hepatic Ndst1-deficiency did not alter hepatic PCSK9 or LDLR (LDL receptor) expression.

Conclusions: The clearance rate of plasma LDL-bound PCSK9 is slower than the clearance rate of its free form. The HSPG syndecan-1 modestly contributes to PCSK9 clearance through an LDLR-independent pathway.