PCSK9 targets important for lipid metabolism

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Ischemic heart disease is the main cause of death worldwide and it is accelerated by increased low-density lipoprotein (LDL) cholesterol (LDL-C) and/or lipoprotein (a) (Lp(a)) concentrations. Proprotein convertase subtilisin/kexin type 9 (PCSK9) alters both LDL-C and in part Lp(a) concentrations through its ability to induce degradation of the LDL receptor (LDLR). PCSK9, however, has additional targets which are potentially involved in lipid metabolism regulation such as the very low density lipoprotein receptor (VLDL), CD36 (cluster of differentiation 36) and the epithelial cholesterol transporter (NPC1L1) and it affects expression of apolipoprotein B48. The PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Many comorbidities (kidney insufficiency, hypothyreoidism, hyperinsulinemia, inflammation) modify PCSK9 expression and release. Two humanized antibodies directed against extracellular PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics (such as silencing RNA) are already in clinical trials. Their results demonstrate a significant reduction in both LDL-C and Lp(a) concentrations – independent of the concomitant medication – and one of them reduced plaque size in high risk cardiovascular patients; results of two ongoing large clinical endpoints studies are awaited. In this review, we summarize and discuss the recent biological data on PCSK9, the regulation of PCSK9, and finally briefly summarize the data of recent clinical studies in the context of lipid metabolism.

Related collections

Most cited references 60

Record: found
Abstract: found
Article: not found

Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab.

Gerald F M Watts, Michael Rocco, David Sullivan … (2014)

This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses. Statin intolerance, which is predominantly due to muscle-related side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients. The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) trial was a 12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12, and at week 12. Three hundred seven patients (age 62 ± 10 years; LDL-C 193 ± 59 mg/dl) were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p <0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups. Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant. (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; NCT01763905). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

0 comments Cited 151 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.

Khek Yu Ho, Shirya Rashid, Yuriy Bashmakov … (2005)

PCSK9 encodes proprotein convertase subtilisin/kexin type 9a (PCSK9), a member of the proteinase K subfamily of subtilases. Missense mutations in PCSK9 cause an autosomal dominant form of hypercholesterolemia in humans, likely due to a gain-of-function mechanism because overexpression of either WT or mutant PCSK9 reduces hepatic LDL receptor protein (LDLR) in mice. Here, we show that livers of knockout mice lacking PCSK9 manifest increased LDLR protein but not mRNA. Increased LDLR protein led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels (46 mg/dl in Pcsk9(-/-) mice versus 96 mg/dl in WT mice). Statins, a class of drugs that inhibit cholesterol synthesis, increase expression of sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor that activates both the Ldlr and Pcsk9 genes. Statin administration to Pcsk9(-/-) mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma. These data demonstrate that PCSK9 regulates the amount of LDLR protein in liver and suggest that inhibitors of PCSK9 may act synergistically with statins to enhance LDLRs and reduce plasma cholesterol.

0 comments Cited 151 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Genetic and metabolic determinants of plasma PCSK9 levels.

Aileen C. Cohen, Helen H. Hobbs, Thomas Lagace … (2009)

PCSK9 is a secreted protein that influences plasma levels of low-density lipoprotein cholesterol (LDL-C) and susceptibility to coronary heart disease. PCSK9 is present in human plasma, but the factors that contribute to differences in plasma concentrations of PCSK9 and how they impact on the levels of lipoproteins have not been well-characterized. The aim of the study was to measure PCSK9 levels in a large, ethnically diverse population (n = 3138) utilizing a sensitive and specific sandwich ELISA. We conducted an observational study in the Dallas Heart Study, a multiethnic, probability-based sample of Dallas County. Plasma levels of PCSK9 varied over approximately 100-fold range (33-2988 ng/ml; median, 487 ng/ml). Levels were significantly higher in women (517 ng/ml) than in men (450 ng/ml), and in postmenopausal women compared to premenopausal women (P < 0.0001), irrespective of estrogen status. Plasma levels of PCSK9 correlated with plasma levels of LDL-C (r = 0.24) but explained less than 8% of the variation in LDL-C levels (r(2) = 0.073). Other factors that correlated with PCSK9 levels included plasma levels of triglycerides, insulin, and glucose. Individuals with loss-of-function mutations in PCSK9 and reduced plasma levels of LDL-C also had significantly lower plasma levels of PCSK9 after adjusting for age, gender, and LDL-C levels (P < 0.0001). Multiple metabolic and genetic factors contribute to variation in plasma levels of PCSK9 in the general population. Although levels of PCSK9 correlate with plasma levels of LDL-C, they account for only a small proportion of the variation in the levels of this lipoprotein.

0 comments Cited 131 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Rainer Schulz: +49-641-9947240 , +49-641-9947239 , rainer.schulz@physiologie.med.uni-giessen.de

Journal

Journal ID (nlm-ta): Clin Res Cardiol Suppl

Journal ID (iso-abbrev): Clin Res Cardiol Suppl

Title: Clinical Research in Cardiology Supplements

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 1861-0706

ISSN (Electronic): 1861-0714

Publication date (Electronic): 7 February 2017

Publication date PMC-release: 7 February 2017

Publication date (Print): 2017

Volume: 12

Issue: Suppl 1

Pages: 2-11

Affiliations

ISNI 0000 0001 2165 8627, GRID grid.8664.c, Department of Physiology, , Justus-Liebig-Universität, ; Aulweg 129, 35392 Giessen, Germany

Article

Publisher ID: 85

DOI: 10.1007/s11789-017-0085-0

PMC ID: 5352789

PubMed ID: 28176216

SO-VID: 5da7c94b-b404-47eb-a737-b2220e063129

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Custom metadata

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: low density lipoprotein (ldl),ldl receptor,lipoprotein (a)

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: low density lipoprotein (ldl), ldl receptor, lipoprotein (a)

Comments

Comment on this article

scite_

Cited by 23

See all cited by

Most referenced authors 1,024

See all reference authors

PCSK9 targets important for lipid metabolism

Read this article at

Abstract

Related collections

Cardiovascular Innovations and Applications

Most cited references 60

Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab.

Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.

Genetic and metabolic determinants of plasma PCSK9 levels.

Author and article information

Contributors

Journal

Affiliations

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 647

Cited by 23

Most referenced authors 1,024