scholarly journals PCSK9 Biology and Its Role in Atherothrombosis

2021 ◽  
Vol 22 (11) ◽  
pp. 5880
Author(s):  
Cristina Barale ◽  
Elena Melchionda ◽  
Alessandro Morotti ◽  
Isabella Russo
Keyword(s):  
Ldl Receptor ◽  
Passive Immunization ◽  
Lipoprotein Metabolism ◽  
Cholesterol Homeostasis ◽  
Proprotein Convertase ◽  
Clinical Value ◽  
Ldl Particles ◽  
First Case ◽  
Current Therapies ◽  
Pcsk9 Inhibition

It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action.

Statins, PCSK9 inhibitors and cholesterol homeostasis: a view from within the hepatocyte

2017 ◽  
Vol 131 (9) ◽  
pp. 791-797 ◽  
Author(s):  
Allan D. Sniderman ◽  
Robert Scott Kiss ◽  
Thomas Reid ◽  
George Thanassoulis ◽  
Gerald F. Watts
Keyword(s):  
Channel Model ◽  
Ldl Receptor ◽  
Cholesterol Homeostasis ◽  
Lower Plasma ◽  
Pcsk9 Inhibitors ◽  
Tracer Studies ◽  
Conventional Model ◽  
Isotope Tracer ◽  
Ldl Particles ◽  
Receptor Number

Statins and PCSK9 inhibitors dramatically lower plasma LDL levels and dramatically increase LDL receptor number within hepatocyte cell membranes. It seems self-evident that total clearance of LDL particles from plasma and total delivery of cholesterol to the liver must increase in consequence. However, based on the results of stable isotope tracer studies, this analysis demonstrates the contrary to be the case. Statins do not change the production rate of LDL particles. Accordingly, at steady state, the clearance rate cannot change. Because LDL particles contain less cholesterol on statin therapy, the delivery of cholesterol to the liver must, therefore, be reduced. PCSK9 inhibitors reduce the production of LDL particles and this further reduces cholesterol delivery to the liver. With both agents, a larger fraction of a smaller pool is removed per unit time. These findings are inconsistent with the conventional model of cholesterol homeostasis within the liver, but are consistent with a new model of regulation, the multi-channel model, which postulates that different lipoprotein particles enter the hepatocyte by different routes and have different metabolic fates within the hepatocyte. The multi-channel model, but not the conventional model, may explain how statins and PCSK9 inhibitors can produce sustained increases in LDL receptor number.

scholarly journals Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): Lessons Learned from Patients with Hypercholesterolemia

2014 ◽  
Vol 60 (11) ◽  
pp. 1380-1389 ◽  
Author(s):  
Zuhier Awan ◽  
Alexis Baass ◽  
Jacques Genest
Keyword(s):  
Viral Entry ◽  
Secretory Pathway ◽  
Ldl Receptor ◽  
Lessons Learned ◽  
Regulatory Control ◽  
Hepatic Tissue ◽  
Loss Of Function ◽  
Proprotein Convertase ◽  
Ldl Particles

BACKGROUND Identification of the proprotein convertase subtilisin/kexin type 9 (PCSK9) as the third gene causing familial hypercholesterolemia (FH) and understanding its complex biology has led to the discovery of a novel class of therapeutic agents. CONTENT PCSK9 undergoes autocatalytic cleavage in the endoplasmic reticulum and enters the secretory pathway. The PCSK9 gene is under the regulatory control of sterol receptor binding proteins 1 and 2. Statins increase PCSK9 and this may modulate the response to this class of medications. In plasma, PCSK9 binds to the epidermal growth factor–like domain of the LDL receptor (LDL-R) on the cell and, once incorporated in the late endosomal pathway, directs the LDL-R toward lysosomal degradation rather than recycling to the plasma membrane. Thus, gain-of-function PCSK9 mutations lead to an FH phenotype, whereas loss-of-function mutations are associated with increased LDL-R–mediated endocytosis of LDL particles and lower LDL cholesterol in plasma. Inhibition of PCSK9 is thus an attractive therapeutic target. Presently, this is achieved by using monoclonal antibodies for allosteric inhibition of the PCSK9–LDL-R interaction. Phase 2 and 3 clinical trials in patients with moderate and severe hypercholesterolemia (including FH) show that this approach is safe and highly efficacious to lower LDL-C and lipoprotein(a). SUMMARY PCSK9 has other biological roles observed in vitro and in animal studies, including viral entry into the cell, insulin resistance, and hepatic tissue repair. Given the potential number of humans exposed to this novel class of medications, careful evaluation of clinical trial results is warranted.

scholarly journals Lipid Disorders and Mutations in the APOB Gene

2004 ◽  
Vol 50 (10) ◽  
pp. 1725-1732 ◽  
Author(s):  
Amanda J Whitfield ◽  
P Hugh R Barrett ◽  
Frank M van Bockxmeer ◽  
John R Burnett
Keyword(s):  
Ldl Receptor ◽  
Lipoprotein Metabolism ◽  
Plasma Lipoproteins ◽  
Premature Coronary Artery Disease ◽  
Missense Mutations ◽  
Apob Gene ◽  
Apo B ◽  
Ldl Particles ◽  
Genetic Features ◽  
Familial Hypobetalipoproteinemia

Abstract Background: Plasma lipoproteins are important determinants of atherosclerosis. Apolipoprotein (apo) B is a large, amphipathic glycoprotein that plays a central role in human lipoprotein metabolism. Two forms of apoB are produced from the APOB gene by a unique posttranscriptional editing process: apoB-48, which is required for chylomicron production in the small intestine, and apoB-100, required for VLDL production in the liver. In addition to being the essential structural component of VLDL, apoB-100 is the ligand for LDL-receptor-mediated endocytosis of LDL particles. Content: The study of monogenic dyslipidemias has revealed important aspects of metabolic pathways. In this review, we discuss the regulation of apoB metabolism and examine how APOB gene defects can lead to both hypo- and hypercholesterolemia. The key clinical, metabolic, and genetic features of familial hypobetalipoproteinemia and familial ligand-defective apoB-100 are described. Summary: Missense mutations in the LDL-receptor-binding domain of apoB cause familial ligand-defective apoB-100, characterized by hypercholesterolemia and premature coronary artery disease. Other mutations in APOB can cause familial hypobetalipoproteinemia, characterized by hypocholesterolemia and resistance to atherosclerosis. These naturally occurring mutations reveal key domains in apoB and demonstrate how monogenic dyslipidemias can provide insight into biologically important mechanisms.

scholarly journals New Insights Into the Regulation of Lipoprotein Metabolism by PCSK9: Lessons From Stable Isotope Tracer Studies in Human Subjects

2021 ◽  
Vol 12 ◽  
Author(s):  
Qidi Ying ◽  
Dick C. Chan ◽  
Gerald F. Watts
Keyword(s):  
Ldl Cholesterol ◽  
Plasma Lipids ◽  
Human Subjects ◽  
High Risk Patient ◽  
Lipoprotein Metabolism ◽  
Kinetic Studies ◽  
Atherosclerotic Cardiovascular Disease ◽  
Healthy Individuals ◽  
Ldl Particles ◽  
Pcsk9 Inhibition

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a convertase enzyme mostly produced by the liver. It is a key regulator of LDL metabolism because of its ability to enhance degradation of the LDL receptor. PCSK9 also regulates the metabolism of lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins (TRLs). Its key role in modulating atherosclerotic cardiovascular disease (ASCVD) is supported by genetic studies and clinical outcome trials. Kinetic studies provide mechanistic insight into the role of PCSK9 in regulating the physiology and pathophysiology of plasma lipids and lipoproteins. Kinetic data have demonstrated that plasma PCSK9 concentration is inversely associated with the clearance of LDL in men. Gain-of-function mutations of PCSK9 markedly increase plasma LDL-cholesterol concentrations due to impaired LDL-apoB catabolism. Conversely, PCSK9 deficiency results in low LDL-cholesterol associated with enhanced LDL-apoB clearance. Inhibition of PCSK9 with monoclonal antibodies (such as evolocumab or alirocumab) lowers plasma LDL-cholesterol and apoB levels chiefly by upregulating the catabolism of LDL particles in healthy individuals. As monotherapy, PCSK9 inhibitor reduced Lp(a) concentrations by decreasing the production rate. However, as combination therapy, it reduced the plasma concentration of Lp(a) by increasing the fractional catabolism of Lp(a) particles. In statin-treated patients with high Lp(a), PCSK9 inhibition lowers plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. The effect of PCSK9 inhibition on TRL metabolism has been studied in healthy individuals and in patients with type 2 diabetes. These findings suggest that PCSK9 appears to play a less important role in TRL than LDL metabolism. Kinetic studies of PCSK9 inhibition therapy on lipoprotein metabolism in diverse high risk patient populations (such as familial hypercholesterolemia) and new therapeutic combination also merit further investigation.

Abstract 452: Detailed Characterization of the Role of the Epidermal Growth Factor Precursor Homology Domain A of the Low-density Lipoprotein Receptor in Proprotein Convertase Subtilisin/kexin-type 9 Binding

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Da-Wei Zhang ◽  
Ayinuer Adijiang ◽  
Hong-mei Gu
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Surface ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Dependent Manner ◽  
Proprotein Convertase ◽  
Epidermal Growth

Proprotein convertase subtilisin/kexin-type 9 (PCSK9) promotes the LDL receptor (LDLR) degradation, thereby preventing clearance of LDL-C levels and playing a central regulatory role in cholesterol homeostasis. PCSK9 interacts with the LDLR at the cell surface and binds the receptor with a much higher affinity at the acidic environment of the endosome. Consequently, the receptor traffics from the endosome to the lysosome for degradation, rather than being recycled. Previously, we have shown that the epidermal growth factor precursor homology domain A (EGF-A) of the LDLR is critical for PCSK9 binding at the cell surface (pH7.4) and that leucine at the position 318 in the EGF-A is critical for PCSK9 binding. Here, we further characterized the role of EGF-A in the binding of PCSK9 to the LDLR in more details. We found that mutation of Asp299 to Val or Arg329 to Pro in the EGF-A significantly reduced PCSK9 binding at pH 7.4. In addition, we observed that deletion of EGF-A significantly reduced PCSK9 binding at the acidic endosomal environment (pH 6.0) and that PCSK9 bound to purified recombinant EGF-A in a pH-dependent manner with a stronger binding at pH6.0. However, mutation of Leu318 to Arg or His306 to Tyr that dramatically enhanced PCSK9 binding at pH7.4 had no significant effect on the binding of PCSK9 to the LDLR at pH6.0. Thus, our findings demonstrate that EGF-A of the LDLR plays an important role in PCSK9 binding at the cell surface (pH 7.4) and the endosomal environment (pH6.0). Our data also indicate that different amino acid residues in EGF-A are involved in PCSK9 binding to the LDLR at the cell surface and in the endosome.

Receptor interactions controlling lipoprotein metabolism

1985 ◽  
Vol 63 (8) ◽  
pp. 898-905 ◽  
Author(s):  
Karl H. Weisgraber ◽  
Thomas L. Innerarity ◽  
Stanley C. Rall Jr. ◽  
Robert W. Mahley
Keyword(s):  
Receptor Binding ◽  
Cholesterol Metabolism ◽  
Ldl Receptor ◽  
Lipoprotein Metabolism ◽  
Binding Domain ◽  
Cholesterol Homeostasis ◽  
Lipoprotein Receptor ◽  
Receptor Binding Domain ◽  
Apo B ◽  
Apo E

Lipoprotein receptors play a central role in lipoprotein metabolism and a major role in cholesterol homeostasis. The most completely characterized lipoprotein receptor is the LDL (low density lipoprotein) or apo-B,E(LDL) receptor. The apo-B,E(LDL) receptor is present on both hepatic and extrahepatic cells and is responsible for the metabolism of a major portion of plasma LDL. Binding and internalization of LDL particles by this receptor initiates a series of intracellular events, resulting in the regulation of cellular cholesterol metabolism. In addition to the apo-B on LDL interacting with the apo-B,E(LDL) receptor, the apo-E on apo-E-containing lipoproteins is also capable of interacting and regulating intracellular cholesterol metabolism. The liver has also been shown to contain a second distinct lipoprotein receptor that is specific for apo-E. This receptor has been demonstrated on hepatic membranes from humans, dogs, and swine and is referred to as the apo-E receptor. This receptor may be responsible for the clearance of chylomicron remnants from plasma by the liver and may participate in reverse cholesterol transport. Thus, apo-E is a major determinant in lipoprotein metabolism and cholesterol homeostasis. The receptor binding properties of apo-E are well characterized, and a series of structural variants, several with lipoprotein binding defects, have been identified. Studies of the binding activity of these receptor-defective apo-E variants have helped to define the receptor binding domain of apo-E. These results, in conjunction with receptor binding studies with various apo-E fragments and with an apo-E monoclonal antibody that inhibits receptor binding, have demonstrated that the receptor binding domain is located in the center of the molecule between residues 140 and 160.

Abstract 129: Effects of a Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor, Alirocumab, on Lipid and Lipoprotein Metabolism in Normal Subjects

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Gissette Reyes-Soffer ◽  
Marianna Pavlyha ◽  
Colleen Ngai ◽  
Paul Ippolito ◽  
Stephen Holleran ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Phase 1 ◽  
Ldl Receptor ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Normal Subjects ◽  
New Drugs ◽  
Low Density ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors

Background: Proprotein convertase subtilisin/kexin type (PCSK9) inhibitors are promising new drugs for the treatment of hypercholesterolemia. They inhibit the binding of PCSK9 to the low density lipoprotein (LDL) receptor that, in turn, decreases lysosomal degradation of LDL receptors and increases their numbers on the cell surface. In Phase 2/3 studies, alirocumab significantly lowered plasma levels of LDL-cholesterol (C) and apolipoprotein B (apoB). The mechanism underlying the LDL-C lowering effects of PCSK9 inhibition has not been reported. Method: We enrolled 10 healthy volunteers (4 male, 6 female), into a Phase 1, placebo-controlled, single-blind, single-sequence study to examine the effects of alirocumab, 150 mg administered subcutaneously every two weeks, on lipid and lipoproteins levels and the metabolism of apoB in very low density (VLDL), intermediate density (IDL) and LDL. Subjects received 2 doses of placebo followed by 5 doses of alirocumab. At the end of each treatment period, fasting lipids and lipoprotein levels were measured, and stable isotope studies of the apoB turnover in VLDL, IDL and LDL were performed. Results: Alirocumab significantly reduced plasma levels of total-C by 37% (178.4±34 to 112.7±29 mg/dL), LDL-C by 59% (110.2±25 to 45.5±26 mg/dL), and apoB by 51% (93.6±25 to 45.5±13 mg/dL) compared to placebo. Plasma triglycerides (TG) and HDL-C did not change. Levels of LDL-C, LDL-TG, and LDL-apoB fell by 55.8±10%, 33.9±13%, and 56.0±11%, respectively (all p<0.0001), on alirocumab. The reductions in LDL apoB were explained by a dramatic increase in the fractional clearance rate (FCR) of LDL apoB from 0.50±0.18 on placebo to 1.02±0.35 pools/day on alirocumab (p<0.001) and a trend toward lower LDL apoB production rates on alirocumab (15.1±4.6 vs 12.9±3.3 mg/kg/day; p=0.10). Levels of IDL-C, IDL-TG and IDL-apoB were also reduced significantly and there was a trend toward an increase in IDL apoB FCR on alirocumab (placebo: 9.2±4 vs alirocumab: 10.8±3 pools/day; p=0.06). Additional kinetic parameters will be presented at the meeting. Summary: Alirocumab treatment significantly reduced the levels of IDL and LDL, and these changes were due to increases in the FCRs of these lipoproteins, particularly LDL.

PCSK9 inhibition for LDL lowering and beyond – implications for patients with peripheral artery disease

VASA ◽  
2018 ◽  
Vol 47 (3) ◽  
pp. 165-176 ◽  
Author(s):  
Katrin Gebauer ◽  
Holger Reinecke
Keyword(s):  
Cardiovascular Risk ◽  
Risk Reduction ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Past Century ◽  
Pcsk9 Inhibitors ◽  
Cardiovascular Risk Reduction ◽  
Simultaneous Application ◽  
The Past ◽  
Pcsk9 Inhibition

Abstract. Low-density lipoprotein cholesterol (LDL-C) has been proven to be a causal factor of atherosclerosis and, along with other triggers like inflammation, the most frequent reason for peripheral arterial disease. Moreover, a linear correlation between LDL-C concentration and cardiovascular outcome in high-risk patients could be established during the past century. After the development of statins, numerous randomized trials have shown the superiority for LDL-C reduction and hence the decrease in cardiovascular outcomes including mortality. Over the past decades it became evident that more intense LDL-C lowering, by either the use of highly potent statin supplements or by additional cholesterol absorption inhibitor application, accounted for an even more profound cardiovascular risk reduction. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serin protease with effect on the LDL receptor cycle leading to its degradation and therefore preventing continuing LDL-C clearance from the blood, is the target of a newly developed monoclonal antibody facilitating astounding LDL-C reduction far below to what has been set as target level by recent ESC/EAS guidelines in management of dyslipidaemias. Large randomized outcome trials including subjects with PAD so far have been able to prove significant and even more intense cardiovascular risk reduction via further LDL-C debasement on top of high-intensity statin medication. Another approach for LDL-C reduction is a silencing interfering RNA muting the translation of PCSK9 intracellularly. Moreover, PCSK9 concentrations are elevated in cells involved in plaque composition, so the potency of intracellular PCSK9 inhibition and therefore prevention or reversal of plaques may provide this mechanism of action on PCSK9 with additional beneficial effects on cells involved in plaque formation. Thus, simultaneous application of statins and PCSK9 inhibitors promise to reduce cardiovascular event burden by both LDL-C reduction and pleiotropic effects of both agents.

Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis

2019 ◽  
Vol 20 (10) ◽  
pp. 1029-1040 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Structure And Function ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Proprotein Convertase ◽  
Novel Target ◽  
New Treatments ◽  
And Function

Background:One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy.Methods:We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis.Results:New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis.Conclusion:PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

Sign in / Sign up

Export Citation Format

Share Document