Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role controlling the levels of low-density lipoprotein (LDL) particles that circulate in the bloodstream. Several gain-of-function and loss-of-function mutations in the PCSK9 gene, which occur naturally, have been identified and linked to hypercholesterolemia and hypocholesterolemia, respectively. Studies have demonstrated that PCSK9 acts mainly by enhancing degradation of the LDL receptor (LDLR) protein in the liver. Inactivation of PCSK9 in mice reduces plasma cholesterol levels primarily by increasing hepatic expression of LDLR protein and thereby accelerating clearance of circulating LDL cholesterol. Since the loss of a functional PCSK9 in human is not associated with apparent deleterious effects, this protease is becoming an attractive target for lowering plasma LDL cholesterol levels either alone or in combination with statins.
Lopez
Dayami
D
Department of Experimental Therapeutics, Moffitt Cancer Center, Tampa, Florida 33612, USA. dayami.lopez@moffitt.org
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D008078:Cholesterol, LDL / Q000097:blood; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D011973:Receptors, LDL; D015842:Serine Proteinase Inhibitors; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases