Proprotein convertase subtilisin kexin type 9 (PCSK9) belongs to the proprotein 
convertase family. Several studies have demonstrated its involvement in the 
regulation of low-density lipoprotein (LDL) cholesterol levels by inducing the 
degradation of the LDL receptor (LDLR). However, experimental, epidemiologic, 
and pharmacologic data provide important evidence on the role of PCSK9 also on 
high-density lipoproteins (HDLs). In mice, PCSK9 regulates the HDL cholesterol 
(HDL-C) levels by the degradation of hepatic LDLR, thus inhibiting the uptake of 
apolipoprotein (Apo)E-containing HDLs. Several epidemiologic and genetic studies 
reported positive relationship between PCSK9 and HDL-C levels, likely by 
reducing the uptake of the ApoE-containing HDL particles. PCSK9 enhances also 
the degradation of LDLR's closest family members, ApoE receptor 2, very 
low-density lipoprotein receptor, and LDLR-related protein 1. This feature 
provides a molecular mechanism by which PCSK9 may affect HDL metabolism. 
Experimental studies demonstrated that PCSK9 directly interacts with HDL by 
modulating PCSK9 self-assembly and its binding to the LDLR. Finally, the 
inhibition of PCSK9 by means of monoclonal antibodies directed to PCSK9 (ie, 
evolocumab and alirocumab) determines an increase of HDL-C fraction by 7% and 
4.2%, respectively. Thus, the understanding of the role of PCSK9 on HDL 
metabolism needs to be elucidated with a particular focus on the effect of PCSK9 
on HDL-mediated reverse cholesterol transport.