title: On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects.
abstract: Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulatory ligand that terminates the lifecycle of the low-density lipoprotein (LDL) receptor (LDLR) thus affecting plasma LDL-cholesterol (LDL-C) levels. Recent evidence shows that in addition to the straightforward mechanism of action, there are more complex interactions between PCSK9, LDLR and plasma lipoprotein levels, including: (a) the presence of both parallel and reciprocal regulation of surface LDLR and plasma PCSK9; (b) a correlation between PCSK9 and LDL-C levels dependent not only on the fact that PCSK9 removes hepatic LDLR, but also due to the fact that up to 40% of plasma PCSK9 is physically associated with LDL; and (c) an association between plasma PCSK9 production and the assembly and secretion of triglyceride-rich lipoproteins. The effect of PCSK9 on LDLR is being successfully utilized toward the development of anti-PCSK9 therapies to reduce plasma LDL-C levels. Current biochemical research has uncovered additional mechanisms of action and interacting partners for PCSK9, and this opens the way for a more thorough understanding of the regulation, metabolism, and effects of this interesting protein.
authors.affiliation: The Knight Cardiovascular Institute, Center of Preventive Cardiology, Oregon Health and Sciences University, Portland, OR, USA.
authors.forename: Hagai
authors.initials: H
authors.lastname: Tavori
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, and Saint John, New Brunswick, Canada.
authors.forename: Shirya
authors.initials: S
authors.lastname: Rashid
authors.affiliation: The Knight Cardiovascular Institute, Center of Preventive Cardiology, Oregon Health and Sciences University, Portland, OR, USA. Electronic address: fazio@ohsu.edu.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006706:Homeostasis; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects; D058990:Molecular Targeted Therapy; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D011485:Protein Binding; D011973:Receptors, LDL / Q000097:blood / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000097:blood / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
chemical_list: D008078:Cholesterol, LDL; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D011973:Receptors, LDL; D014280:Triglycerides; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Low-density lipoprotein; Low-density lipoprotein receptor; Pleiotropic effects; Proprotein convertase subtilisin kexin 9; Protein interaction