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Principal Investigator: SERGIO FAZIO
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2019
Award: $533,826
Funding agency: National Heart Lung and Blood Institute
Summary
Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulatory protein that binds to the low-density
lipoprotein receptor (LDLR), induces its degradation, and increases LDL-cholesterol (LDL-C) levels. Thus,
PCSK9 is a therapeutic target to increase LDLR expression and reduce plasma LDL-C levels, and PCSK9
inhibitors have recently been approved for use in the US and Europe. Plasma PCSK9 levels are highly
correlated to LDL-C levels, both because elevated PCSK9 levels increase plasma LDL levels by decreasing
LDLR and because up to 40% of plasma PCSK9 is physically associated with LDL, a discovery initially made in
our laboratory and later confirmed by others. Plasma PCSK9 is found in two main forms, an intact form (62
kDa) and a furin-cleaved form (55 kDa). We show that PCSK9 associated with LDL is mainly in the intact 62-
kDa form, whereas the rest of plasma PCSK9 is mainly as the 55 kDa furin-cleaved fragment. The intact, LDL-
associated PCSK9 seems to have an increased capacity to bind and degrade LDLR. Our preliminary results
also suggest that LDL protects PCSK9 from cleavage by furin. However, it is still unclear what drives the
compartmentalization of the molecular forms of circulating PCSK9, and whether there are functional correlates
to this compartmentalization. Thus, we propose studies to clarify the connection between plasma PCSK9
forms, molecular drivers of their lipoprotein association, and LDLR degradation activity. Moreover, we propose
to develop a high-throughput method to detect LDL-bound PCSK9 in plasma and to study PCSK9 association
with other apoB-containing lipoproteins, such as Lp(a), and with intracellular apoB. Finally, we will study the
mechanisms leading to the unexpectedly large time delay between the initial PCSK9-LDLR contact and the
eventual degradation of the LDLR, as this seems to be due to a complex intracellular routing of PCSK9 which
includes a re-secretion/recycling step. The central hypothesis of this proposal is that LDL carries a significant
portion of the intact plasma PCSK9 form (62 kDa), which may behave differently in LDLR binding and
degradation compared with the other major form of plasma PCSK9 (55 kDa). The results from these studies
will enhance our understanding of both the physiologic role of PCSK9 association with lipoproteins and the
mechanism by which PCSK9 inhibition produces therapeutic gains, and may inform alternative strategies to
inhibit the effect of PCSK9 on LDLR through interruption of PCSK9 association with lipoproteins.
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Terms: <ANGPT5><ANGPTL3><ANGPTL3 gene><Amino Acids><Anthelone U><Apo-B><ApoB><Apolipoproteins B><Assay><Binding><Binding Proteins><Bioassay><Biologic Assays><Biological Assay><Blocking Antibodies><Blood Plasma><Cardiac infarction><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cholesterol><Cleaved cell><Clinical><Complex><Dyslipidemias><Enzyme Gene><Enzymes><Epidermal Growth Factor><Epidermal Growth Factor-Urogastrone><Europe><Event><Genetic Alteration><Genetic Change><Genetic defect><Heart Vascular><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hereditary><Hour><Inherited><Interruption><LDL><LDL Cholesterol><LDL Cholesterol Lipoproteins><LDL Lipoproteins><LDL Receptors><Laboratories><Ligand Binding Protein><Ligand Binding Protein Gene><Lipoprotein (a)><Lipoprotein LDL Receptors><Lipoprotein Lp(a)><Lipoproteins><Liver Cells><Low Density Lipoprotein Cholesterol><Low Density Lipoprotein Receptor><Low-Density Lipoproteins><Lp(a)><Mediating><Methods><Molecular><Molecular Interaction><Mutation><Myocardial Infarct><Myocardial Infarction><N-terminal><NH2-terminal><Pathway interactions><Physiologic><Physiological><Plasma><Plasma Serum><Play><Process><Production><Property><Proprotein Convertases><Protein Binding><Proteins><Recycling><Regulation><Rest><Reticuloendothelial System, Serum, Plasma><Role><Route><Structure><Subtilisins><Surface><Syndrome><Therapeutic><Time><Urogastrone><Work><aminoacid><angiopoietin 5><angiopoietin-like 3><base><beta-Lipoprotein Cholesterol><beta-Lipoproteins><beta-Urogastrone><bound protein><cardiac infarct><cholesterol control><cholesterol management><cholesterol trafficking><circulatory system><cleaved><clinical relevance><clinically relevant><cohort><coronary attack><coronary infarct><coronary infarction><genome mutation><heart attack><heart infarct><heart infarction><inhibitor><inhibitor/antagonist><manage cholesterol><mutation carrier><neutralizing antibody><particle><pathway><prevent><preventing><receptor binding><receptor bound><receptor expression><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><uptake>