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PCSK9
PCSK9 proprotein convertase subtilisin/kexin type (PCSK9) is a crucial protein in LDL cholesterol (LDL-C) metabolism by virtue of its pivotal role in the degradation of the LDL receptor. PCSK9 acts by reducing the amount of LDLR at the cell surface of hepatocytes. Numerous overexpression and knockdown/knockout animal studies clearly show that PCSK9 targets the LDLR for degradation. Probably the most elegant demonstration came from a series of parabiosis experiments showing that PCSK9 is secreted from liver cells, circulates in the plasma, binds to LDLR, and is subsequently internalized together with the LDLR, thereby promoting the cellular degradation of the receptor. PCSK9 is a serine protease encoded by a gene comprising 12 exons, located on chromosome 1p32.3. It is synthesized primarily by the liver and intestine as a 692-amino acid precursor (∼75 kDa) in which a signal peptide (residues 1–30) and a prodomain (residues 31–152) precede a catalytic domain (residues 153–451) that contains the canonical D-H-S catalytic triad, followed by a C-terminal domain (residues 452–692).
The region where secreted PCSK9 interacts with the extracellular domain of the LDLR is located in the first epidermal growth factor-like repeat homology domain (EGFA) of the human LDLR. Similar to LDLR, the expression of PCSK9 is modulated by intracellular cholesterol levels, and this is mediated predominantly by the transcription factor sterol-responsive element-binding protein 2 (SREBP2) . The transcription factor hepatocyte nuclear factor 1a (HNF1a) has also been shown to be a potent stimulator of PCSK9 gene expression. Because PCSK9 and the LDLR are coordinately regulated at the transcriptional level by cholesterol, they are also coinduced by statin treatment. PCSK9 inhibition is considered an attractive target for therapy, especially in light of the fact that a large proportion of high-risk patients do not reach the target LDL-C levels despite maximally tolerated forms of currently available lipid-lowering agents. Monoclonal antibodies are currently the most advanced PCSK9 inhibitors in terms of pharmacological development.
References
1.Lambert G,et al. J Lipid Res. 2012;53(12):2515–2524.
The region where secreted PCSK9 interacts with the extracellular domain of the LDLR is located in the first epidermal growth factor-like repeat homology domain (EGFA) of the human LDLR. Similar to LDLR, the expression of PCSK9 is modulated by intracellular cholesterol levels, and this is mediated predominantly by the transcription factor sterol-responsive element-binding protein 2 (SREBP2) . The transcription factor hepatocyte nuclear factor 1a (HNF1a) has also been shown to be a potent stimulator of PCSK9 gene expression. Because PCSK9 and the LDLR are coordinately regulated at the transcriptional level by cholesterol, they are also coinduced by statin treatment. PCSK9 inhibition is considered an attractive target for therapy, especially in light of the fact that a large proportion of high-risk patients do not reach the target LDL-C levels despite maximally tolerated forms of currently available lipid-lowering agents. Monoclonal antibodies are currently the most advanced PCSK9 inhibitors in terms of pharmacological development.
References
1.Lambert G,et al. J Lipid Res. 2012;53(12):2515–2524.