PCSK9 Function and Potential Targets for Therapeutics
SREBP-2 in hepatocytes regulates transcription of several lipids and proteins, including the low-density lipoprotein receptor (LDL-R) and proprotein convertase subtilisin/kexin type 9 (PCSK9) (step 1). PCSK9 is processed in the endoplasmic reticulum into a mature form (step 2) and undergoes packaging by the Golgi apparatus (as does the LDL-R) before being secreted (step 3). The LDL-R binds circulating low-density lipoprotein cholesterol (LDL-C) (step 4), and the pair is internalized in endosomes, where LDL-C can be shuttled for other use. Meanwhile, the LDL-R recirculates to the cell surface (step 5) up to 150 times, removing additional LDL-C from the circulation. PCSK9 regulates the number of LDL-R by binding to and internalizing the LDL-R (step 6), escorting it to its destruction in the lysosome (step 7). This does not permit the LDL-R to recirculate. Several methods to interfere with the function of PCSK9 are shown by the letters within red octagons. Small interfering ribonucleic acids (siRNAs) (A) can block transcription of PCSK9 messenger ribonucleic acid, whereas small molecular inhibitors (B) can disrupt the processing of PCSK9—both approaches reduce the production of functional PCSK9. Two extracellular approaches to inhibit PCSK9 function include monoclonal antibodies (MoAbs) (C) and adnectins (D) that prevent binding of PCSK9 to the LDL-R. SREBP = sterol-binding regulatory element-binding transcription factor.