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.