OBJECTIVE: proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively 
regulates the low-density lipoprotein (LDL) receptor (LDLR) in hepatocytes and 
therefore plays an important role in controlling circulating levels of 
LDL-cholesterol. To date, the relationship between PCSK9 and metabolism of 
apolipoprotein B (apoB), the structural protein of LDL, has been controversial 
and remains to be clarified.
METHODS AND RESULTS: We assessed the impact of PCSK9 overexpression (≈400-fold 
above baseline) on apoB synthesis and secretion in 3 mouse models: wild-type 
C57BL/6 mice and LDLR-null mice (Ldlr(-/-) and Ldlr(-/-)Apobec1(-/-)). 
Irrespective of LDLR expression, mice transduced with the PCSK9 gene invariably 
exhibited increased levels of plasma cholesterol, triacylglycerol, and apoB. 
Consistent with these findings, the levels of very-low-density lipoprotein and 
LDL were also increased whereas high-density lipoprotein levels were unchanged. 
Importantly, we demonstrated that endogenous PCSK9 interacted with apoB in 
hepatocytes. The PCSK9/apoB interaction resulted in increased production of 
apoB, possibly through the inhibition of intracellular apoB degradation via the 
autophagosome/lysosome pathway.
CONCLUSIONS: We propose a new role for PCSK9 that involves shuttling between 
apoB and LDLR. The present study thus provides new insights into the action of 
PCSK9 in regulating apoB metabolism. Furthermore, our results indicate that 
targeting PCSK9 expression represents a new paradigm in therapeutic intervention 
against hyperlipidemia.