OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds 
the low-density lipoprotein receptor and targets it for degradation, has emerged 
as an important regulator of serum cholesterol levels and cardiovascular disease 
risk. Although much work is currently focused on developing therapies for 
inhibiting PCSK9, the endogenous regulation of PCSK9, particularly by insulin, 
remains unclear. The objective of these studies was to determine the effects of 
insulin on PCSK9 in vitro and in vivo.
APPROACH AND RESULTS: Using rat hepatoma cells and primary rat hepatocytes, we 
found that insulin increased PCSK9 expression and increased low-density 
lipoprotein receptor degradation in a PCSK9-dependent manner. In parallel, 
hepatic Pcsk9 mRNA and plasma PCSK9 protein levels were reduced by 55% to 75% in 
mice with liver-specific knockout of the insulin receptor; 75% to 88% in mice 
made insulin-deficient with streptozotocin; and 65% in ob/ob mice treated with 
antisense oligonucleotides against the insulin receptor. However, antisense 
oligonucleotide-mediated knockdown of insulin receptor in lean, wild-type mice 
had little effect. In addition, we found that fasting was able to reduce PCSK9 
expression by 80% even in mice that lack hepatic insulin signaling.
CONCLUSIONS: Taken together, these data indicate that although insulin induces 
PCSK9 expression, it is not the sole or even dominant regulator of PCSK9 under 
all conditions.