Mouse Proprotein Convertase 9/PCSK9 Quantikine ELISA Kit Best Seller

The primary physiologic function of PCSK9 is to mediate the degradation of low density lipoprotein receptor (LDLR). Early observations indicated that gain-of-function missense mutations in the human PCSK9 gene can cause an autosomal dominant form of hypercholesterolemia (7, 8). The expression of PCSK9 is also upregulated by the sterol regulatory element binding proteins (SREBPs), a family of transcription factors that are responsible for the upregulation of genes involved in cholesterol and fatty acid metabolism, such as the LDLR gene (9, 10). Further experimental evidence revealed that when the mouse PCSK9 gene is deleted, LDLR expression in hepatocytes is increased. Conversely, PCSK9 over-expression decreases liver LDLR protein expression (11, 12). In humans, genetic analyses have shown that individuals who have nonsense or loss-of-function mutations in the PCSK9 gene have significantly lower plasma LDL cholesterol levels, while in mouse, administration of a PCSK9 neutralizing antibody or antisense oligonucleotides lowers serum cholesterol (1, 13-15). These investigations clearly indicate that PCSK9 plays a key role in reducing the hepatic LDLR levels. Paradoxically, administration of cholesterol-lowering drugs such as statins appear to enhance production of PCSK9 (6). 

The underlying mechanism of cholesterol regulation by PCSK9 is as follows: under normal physiologic conditions, the LDLR is internalized at the cell surface and directed to the endosomes in order to be recycled back to the cell surface. PCSK9 binds to the EGF domain of the LDLR and prevents LDLR from being sorted to the endosomes. Instead, the PCSK9/LDLR complex is redistributed to the lysosomes for degradation (16-18). As such, PCSK9 regulates the amount of LDLR in the circulation and hence, modulates cholesterol levels. Serum PCSK9 concentrations have been found to be directly associated with cholesterol levels (19, 20). Since PCSK9 loss-of-function mutations strikingly reduce risk of coronary heart diseases, PCSK9 has become an attractive drug target (1, 21, 22). One approach is to generate small molecules that are able to interfere with PCSK9 autoactivation and its interaction with LDLR. Other approaches aiming to reduce the amount of PCSK9 in the circulation, such as small interfering RNAs (siRNAs), have also shown promise (23, 24).