PCSK9 and Lipoprotein(a)
The Plot Thickens
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Proprotein convertase subtilisin kexin type 9 (PCSK9) has rapidly become a focus of intensive investigation worldwide because of its linkage to multiple clinically important facets of hepatic lipoprotein metabolism. To facilitate secretion and proper folding, the zymogen pro-PCSK9 must undergo autocatalytic cleavage. Once in the extracellular space, mature PCSK9 does not engage in proteolytic activity because its active site is blocked by a prosegment.1 PCSK9 modulates the expression of a variety of cell surface receptors regulating lipoprotein and lipid trafficking across the cell membrane. Initial studies that lead to the identification of PCSK92 correlated 2 novel gain-of-function mutations in this enzyme with the phenotype of autosomal dominant hypercholesterolemia (familial hypercholesterolemia).3 Subsequent to these discoveries, loss-of-function mutations in PCSK9 were found to correlate with low serum levels of low-density lipoprotein cholesterol (LDL-C) and reduced risk for future cardiovascular events.4 Given these findings, PCSK9 has become an important therapeutic target in the management of dyslipidemia, and 2 monoclonal antibodies directed against it have recently been approved for use in patients with elevated LDL-C.
Article, see p 29
Much recent work has focused on how PCSK9 regulates the expression of the LDL receptor (LDLR). Once secreted into the extracellular milieu, PCSK9 can bind to a complex composed of the LDLR and an LDL particle. This binding occurs between the catalytic surface of PCSK95 and the epidermal growth factor–like repeat A domain of LDLR.6 The resulting complex is incorporated into clathrin-coated endosomal vesicles. The role of PCSK9 is to then chaperone the LDLR complex into the lysosome for hydrolytic destruction via an endosomal pathway, thereby reducing the recycling of LDLR to the hepatocyte cell surface and reducing LDL particle clearance capacity. This model neatly explains why gain-of-function and loss-of-function mutations would be etiologic for elevations and reductions in …