title: Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering.
abstract: Proprotein convertase subtilisin kexin 9 (PCSK9) is a key regulator of low-density lipoprotein receptor levels and LDL-cholesterol levels. Loss-of-function mutations in PCSK9 gene are associated with hypocholesterolaemia and protection against cardiovascular disease, identifying PCSK9 inhibition as a valid therapeutic approach to manage hypercholesterolaemia and related diseases. Although PCSK9 is expressed mainly in the liver, it is present also in other tissues and organs with specific functions, raising the question of whether a pharmacological inhibition of PCSK9 to treat hypercholesterolaemia and associated cardiovascular diseases might be helpful or deleterious in non-hepatic tissues. For example, PCSK9 is expressed in the vascular wall, in the kidneys, and in the brain, where it was proposed to play a role in development, neurocognitive process, and neuronal apoptosis. A link between PCSK9 and immunity was also proposed as both sepsis and viral infections are differentially affected in the presence or absence of PCSK9. Despite the increasing number of observations, the debate on the exact roles of PCSK9 in extrahepatic tissues is still ongoing, and as very effective drugs that inhibit PCSK9 have become available to the clinician, a better understanding of the biological roles of PCSK9 is warranted.
authors: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy Center for the Study of Atherosclerosis, Ospedale Bassini, Cinisello Balsamo, Italy.
authors: Giuseppe Danilo
authors: GD
authors: Norata
authors: Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
authors: Hagai
authors: H
authors: Tavori
authors: Center for the Study of Atherosclerosis, Ospedale Bassini, Cinisello Balsamo, Italy IRCCS Multimedica, Milan, Italy.
authors: Angela
authors: A
authors: Pirillo
authors: Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
authors: Sergio
authors: S
authors: Fazio
authors: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy IRCCS Multimedica, Milan, Italy alberico.catapano@unimi.it.
authors: Alberico L
authors: AL
authors: Catapano
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D008078:Cholesterol, LDL / Q000097:blood*; D003141:Communicable Diseases / Q000201:enzymology; D015536:Down-Regulation; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000924:Anticholesteremic Agents; D015415:Biomarkers; D001786:Blood Glucose; D008078:Cholesterol, LDL; D000091362:PCSK9 Inhibitors; D015842:Serine Proteinase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: APO B; LDL; LDLR; Monoclonal antibodies; PCSK9