The PCSK9 gene at 1p32.3 codes for the precursor 692 amino acid peptide to proprotein convertase 9 (Proprotein convertase subtilisin/kexin type 9). This serine protease is key to the degradation of low-density lipid receptor proteins so regulating plasma cholesterol. It is active on:
- The low density lipoprotein receptor (LDLR)
- The very low density lipoprotein receptor (VLDLR)
- The apolipoprotein E receptor (LRP1/APOER)
- The apolipoprotein receptor 2 (LRP8/APOER2)
It inhibits intracellular degradation of apolipoprotein B-100 via the autophagosome/lysosome pathway as well as regulating neuronal apoptosis via modulation of apolipoprotein receptor 2 levels. With in the cell its processing depends upon autocatalytic cleavage so as to transport it from the endoplasmic reticulum to the Golgi apparatus and for its secretion. In the absence of LDLR it stays in the endoplasmic reticulum but colocalizes to the cell surface and to the endosomes/lysosomes if LDLR is present. This then allows LDLR degradation.
Variations in the PCSK9gene which is close by the APOA2 gene are associated with:
- Hypercholesterolaemia where it can act as a permissive factor
- Familial hypercholesterolaemia 3 (FH3)
- PCSK9 loss-of-function results in 15-30% lower circulating LDL-cholesterol and a markedly lower risk (47-88%) of significant cardiovascular events.
- ↑ Santos RD, Watts GF. Familial hypercholesterolaemia: PCSK9 inhibitors are coming. Lancet. 2014 Oct 1.(Epub ahead of print) (Link to article – subscription may be required.)
- ↑ Ason B, van der Hoorn JW, Chan J, Lee E, Pieterman EJ, Nguyen KK, Di M, Shetterly S, Tang J, Yeh WC, Schwarz M, Jukema JW, Scott R, Wasserman SM, Princen HM, Jackson S. PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE. Journal of lipid research. 2014 Nov; 55(11):2370-9.(Link to article – subscription may be required.)