Serum levels of proprotein convertase subtilisin/kexin type 9 in subjects with familial hypercholesterolemia indicate that proprotein convertase subtilisin/kexin type 9 is cleared from plasma by low-density lipoprotein receptor-independent pathways.

Secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor (LDLR) at the cell surface and disrupts the normal recycling of the LDLR. When human PCSK9 is injected into LDLR-deficient mice, PCSK9 is still rapidly cleared by the liver. This finding may suggest that PCSK9 is physiologically also cleared by receptors other than the LDLR. An alternative explanation could be that PCSK9 has undergone modifications during purification and is cleared by scavenger receptors on liver endothelial sinusoidal cells when injected into mice. If the only mechanism for clearing PCSK9 in humans is through the LDLR, one would expect that differences in the number of LDLRs would affect the plasma levels of low-density lipoprotein cholesterol (LDLC) and PCSK9 in a similar fashion. In this study, levels of LDLC and PCSK9 were measured in familial hypercholesterolemia (FH) homozygotes, FH heterozygotes, and normocholesterolemic subjects. The ratio between the levels of LDLC and PCSK9 was 1.7-fold higher in FH heterozygotes and 3-fold higher in FH homozygotes than in the normocholesterolemic subjects. Thus, defective LDLRs have a greater impact on the levels of LDLC than on the levels of PCSK9. By assuming that the rate of PCSK9 synthesis is similar in the 3 groups, this finding suggests that in humans, plasma PCSK9 is also cleared by LDLR-independent mechanisms.