Since the discovery of PCSK9 in 2003, this proprotein convertase was shown to target specific receptors for degradation in endosomes/lysosomes, including LDLR and other family members and hence to enhance the levels of circulating LDL-cholesterol (LDLc). Accordingly, inhibitors of PCSK9, including monoclonal antibodies blocking its circulating activity and siRNA silencers of its hepatic expression, are now used in clinics worldwide to treat hypercholesterolemia patients effectively and safely in combination with statins and/or ezetimibe. These powerful treatments reduce the incidence of atherosclerosis by at least 20%. Since 2008, novel targets of PCSK9 began to be defined, thereby expanding its roles beyond LDLc regulation into the realm of inflammation, pathogen infections and cellular proliferation in various cancers and associated metastases.
Excerpt citing our work:
"Depletion of ER-Ca2+ results in ER stress and functional activation of SREBP-2 [54] following its processing by the membrane-bound proteases SKI-1/S1P and S2P in the cis/medial Golgi [56, 57]. Notably, both PCSK9 and LDLR mRNA levels are upregulated by the lipid regulating transcription factor SREBP2 [58–60]. To reduce ER stress, Lebeau et al. screened for compounds that enhance ER-entry of Ca2+ and hence augment the stabilization of GRP76 and retention of SREBP-2 in the ER. Amazingly, caffeine and some of its xanthine derivatives were shown to increase hepatic ER Ca2+ levels, and effectively block de novo synthesis of PCSK9, and reduce its circulating levels in vitro, in vivo, and in healthy volunteers [61•]. This resulted in increased expression of the cell surface LDLR protein and clearance of LDLc [61•], reinforcing the notion that loss of extracellular PCSK9 effectively enhances hepatocyte cell-surface LDLR protein levels [62]. These findings delineate a mechanism by which ER Ca2+ and its modulators e.g. caffeine, can affect the expression and activity of proteins that play a pivotal role in CVD."