Proprotein convertase subtilisin/kexin type 9 (PCSK9): Lessons learned from patients with hypercholesterolemia

Clinical Chemistry

Volumn 60, Issue 11, 2014, Pages 1380-1389

  Awan, Zuhier ^a   Baass, Alexis ^b   Genest, Jacques ^b  

^a KING ABDULAZIZ UNIVERSITY   (Saudi Arabia)

^b ROYAL VICTORIA HOSPITAL   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

LOW DENSITY LIPOPROTEIN RECEPTOR; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9; SERINE PROTEINASE; UNCLASSIFIED DRUG; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MONOCLONAL ANTIBODY; PCSK9 PROTEIN, HUMAN;

CATALYSIS; DIET; ENZYME ACTIVITY; ENZYME BLOOD LEVEL; GENETICS; HEALTH CARE QUALITY; HUMAN; HYPERCHOLESTEROLEMIA; INSULIN RESISTANCE; LIVER REGENERATION; MENDELIAN RANDOMIZATION ANALYSIS; METASTASIS; MONOTHERAPY; NONHUMAN; PROTEIN PROCESSING; REVIEW; VIRUS INFECTION; ANIMAL; DISEASE MODEL; ENZYMOLOGY; HYPERLIPOPROTEINEMIA TYPE II; METABOLISM; MUTATION; PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC);

ANIMALS; ANTIBODIES, MONOCLONAL; CHOLESTEROL, LDL; CLINICAL TRIALS, PHASE III AS TOPIC; DISEASE MODELS, ANIMAL; HUMANS; HYPERLIPOPROTEINEMIA TYPE II; MUTATION; PROPROTEIN CONVERTASES; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RECEPTORS, LDL; SERINE ENDOPEPTIDASES;

EID: 84908635367     PISSN: 00099147     EISSN: 15308561     Source Type: Journal    
DOI: 10.1373/clinchem.2014.225946     Document Type: Review

References (70)

1. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A 2003;100:928-33.
2. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154-6.
3. Seidah NG, Prat A. The proprotein convertases are potential targets in the treatment of dyslipidemia. J Mol Med 2007;85:685-96.
4. Davignon J, Dubuc G, Seidah NG. The influence of PCSK9 polymorphisms on serum low-density lipoprotein cholesterol and risk of atherosclerosis. Curr Atheroscler Rep 2010;12:308-15.
5. Zaid A, Roubtsova A, Essalmani R, Marcinkiewicz J, Chamberland A, Hamelin J, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology 2008;48: 646-54.
6. Seidah NG, Mayer G, Zaid A, Rousselet E, Nassoury N, Poirier S, et al. The activation and physiological functions of the proprotein convertases. Int J Biochem Cell Biol 2008;40:1111-25.
7. Chen XW, Wang H, Bajaj K, Zhang P, Meng ZX, Ma D, et al. SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion. Elife 2013;2:e00444.
8. Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, Subashi TA, et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Mol Biol 2007;14:413-9.
9. Piper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, Thibault ST, et al. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure 2007;15:545-52.
10. Seidah NG. PCSK9 as a therapeutic target of dyslipidemia. Expert Opin Ther Targets 2009;13: 19-28.
11. Benjannet S, Rhainds D, Hamelin J, Nassoury N, Seidah NG. The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and posttranslational modifications. J Biol Chem 2006; 281:30561-72.
12. Essalmani R, Susan-Resiga D, Chamberland A, Abifadel M, Creemers JW, Boileau C, et al. In vivo evidence that furin from hepatocytes inactivates PCSK9. J Biol Chem 2011;286:4257-63.
13. Han B, Eacho PI, Knierman MD, Troutt JS, Konrad RJ, Yu X, et al. Isolation and characterization of the circulating truncated form of PCSK9. J Lipid Res 2014;55:1505-14.
14. Kwon HJ, Lagace TA, McNutt MC, Horton JD, Deisenhofer J. Molecular basis for LDL receptor recognition by PCSK9. Proc Natl Acad Sci U S A 2008;105:1820 -5.
15. Kosenko T, Golder M, Leblond G, Weng W, Lagace TA. Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation. J Biol Chem 2013;288:8279-88.
16. Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci U S A 2005; 102:5374-9.
17. Tavori H, Fan D, Blakemore JL, Yancey PG, Ding L, Linton MF, Fazio S. Serum proprotein convertase subtilisin/kexin type 9 and cell surface lowdensity lipoprotein receptor: evidence for a reciprocal regulation. Circulation 2013;127:2403-13.
18. Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, et al. Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. Arterioscler Thromb Vasc Biol 2004;24:1448-53.
19. Sun H, Samarghandi A, Zhang N, Yao Z, Xiong M, Teng BB. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. Arterioscler Thromb Vasc Biol 2012;32:1585-95.
20. Rashid S, Tavori H, Brown PE, Linton MF, He J, Giunzioni I, Fazio S. Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms. Circulation 2014;130:431-41.
21. Lambert G, Jarnoux AL, Pineau T, Pape O, Chetiveaux M, Laboisse C, et al. Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor. Endocrinology 2006;147:4985-95.
22. Zhang DW, Lagace TA, Garuti R, Zhao Z, Mc-Donald M, Horton JD, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem 2007;282: 18602-12.
23. Konrad RJ, Troutt JS, Cao G. Effects of currently prescribed LDL-C-lowering drugs on PCSK9 and implications for the next generation of LDL-Clowering agents. Lipids Health Dis 2011;10:38.
24. Saavedra YG, Day R, Seidah NG. The M2 module of the Cys-His-rich domain (CHRD) of PCSK9 protein is needed for the extracellular low-density lipoprotein receptor (LDLR) degradation pathway. J Biol Chem 2012;287:43492-501.
25. Qian YW, Schmidt RJ, Zhang Y, Chu S, Lin A, Wang H, et al. Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J Lipid Res 2007;48:1488-98.
26. Poirier S, Mayer G, Poupon V, McPherson PS, Desjardins R, Ly K, et al. Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route. J Biol Chem 2009;284:28856-64.
27. Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, Prather HB, et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest 2006; 116:2995-3005.
28. Nassoury N, Blasiole DA, Tebon Oler A, Benjannet S, Hamelin J, Poupon V, et al. The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic 2007;8:718-32.
29. Awan Z, Seidah NG, MacFadyen JG, Benjannet S, Chasman DI, Ridker PM, Genest J. Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clin Chem 2012;58:183-9.
30. Costet P, Cariou B, Lambert G, Lalanne F, Lardeux B, Jarnoux AL, et al. Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. J Biol Chem 2006;281:6211-8.
31. Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004;24:1454-9.
32. Abifadel M, Rabès JP, Devillers M, Munnich A, Erlich D, Junien C, et al. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat 2009;30:520-9.
33. Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, et al. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet 2004; 114:349-53.
34. Shioji K, Mannami T, Kokubo Y, Inamoto N, Takagi S, Goto Y, et al. Genetic variants in PCSK9 affect the cholesterol level in Japanese. J Hum Genet 2004;49:109-14.
35. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264-72.
36. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380:581-90.
37. Awan Z, Delvin EE, Levy E, Genest J, Davignon J, Seidah NG, et al. Regional distribution and metabolic effect of PCSK9 insLEU and R46L gene mutations and apoE genotype. Can J Cardiol 2013;29:927-33.
38. Talmud PJ, Shah S, Whittall R, Futema M, Howard P, Cooper JA, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet 2013;381:1293-301.
39. Marduel M, Ouguerram K, Serre V, Bonnefont-Rousselot D, Marques-Pinheiro A, Erik Berge K, et al. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum Mutat 2013;34:83-7.
40. Awan Z, Choi HY, Stitziel N, Ruel I, Bamimore MA, Husa R, Gagnon MH, et al. APOE p.Leu167del mutation in familial hypercholesterolemia. Atherosclerosis 2013;231:218-22.
41. Lange LA, Hu Y, Zhang H, Xue C, Schmidt EM, Tang ZZ, et al. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. Am J Hum Genet 2014;94:233-45.
42. Peloso GM, Auer PL, Bis JC, Voorman A, Morrison AC, Stitziel NO, et al. Association of lowfrequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am J Hum Genet 2014;94:223-32.
43. Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006;79:514-23.
44. Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia. Curr Opin Lipidol 2014;25:161-8.
45. Dubuc G, Tremblay M, Paré G, Jacques H, Hamelin J, Benjannet S, et al. A new method for measurement of total plasma PCSK9: clinical applications. J Lipid Res 2010;51:140-9.
46. Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab 2009;94:2537-43.
47. Dewpura T, Mayne J. Analyses of PCSK9 posttranslational modifications using time-of-flight mass spectrometry. Methods Mol Biol 2011;768: 167-87.
48. Krastins B, Prakash A, Sarracino DA, Nedelkov D, Niederkofler EE, Kiernan UA, et al. Rapid development of sensitive, high-throughput, quantitative and highly selective mass spectrometric targeted immunoassays for clinically important proteins in human plasma and serum. Clin Biochem 2013;46:399-410.
49. Baass A, Dubuc G, Tremblay M, Delvin EE, O'Loughlin J, Levy E, et al. Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents. Clin Chem 2009;55:1637-45.
50. Peticca P, Raymond A, Gruslin A, Cousins M, Adetola E, Abujrad H, et al. Human serum PCSK9 is elevated at parturition in comparison to nonpregnant subjects while serum PCSK9 from umbilical cord blood is lower compared to maternal blood. ISRN Endocrinol 2013;2013:341632.
51. Persson L, Henriksson P, Westerlund E, Hovatta O, Angelin B, Rudling M. Endogenous estrogens lower plasma PCSK9 and LDL cholesterol but not Lp(a) or bile acid synthesis in women. Arterioscler Thromb Vasc Biol 32:810-4.
52. Richard C, Couture P, Desroches S, Benjannet S, Seidah NG, Lichtenstein AH, Lamarche B. Effect of the Mediterranean diet with and without weight loss on surrogate markers of cholesterol homeostasis in men with the metabolic syndrome. Br J Nutr 2012;107:705-11.
53. Ason B, Tep S, Davis HR Jr, Xu Y, Tetzloff G, Galinski B, et al. Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9. J Lipid Res 2011;52:679-87.
54. Berthold HK, Seidah NG, Benjannet S, Gouni-Berthold I. Evidence from a randomized trial that simvastatin, but not ezetimibe, upregulates circulating PCSK9 levels. PLoS One 2013;8:e60095.
55. Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a lowdensity lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A 2004;101:7100-5.
56. Denis M, Marcinkiewicz J, Zaid A, Gauthier D, Poirier S, Lazure C, et al. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 2012; 125:894-901.
57. Awan Z, Denis M, Bailey D, Giaid A, Prat A, Goltzman D, et al. The LDLR deficient mouse as a model for aortic calcification and quantification by micro-computed tomography. Atherosclerosis 2011;219:455-62.
58. Le May C, Kourimate S, Langhi C, Chétiveaux M, Jarry A, Comera C, et al. Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. Arterioscler Thromb Vasc Biol 2009;29:684-90.
59. Mbikay M, Sirois F, Mayne J, Wang GS, Chen A, Dewpura T, et al. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett 2010;584:701-6.
60. Jonas MC, Costantini C, Puglielli L. PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep 2008;9:916-22.
61. Bassi DE, Mahloogi H, Klein-Szanto AJ. The proprotein convertases furin and PACE4 play a significant role in tumor progression. Mol Carcinog 2000;28:63-9.
62. Sun X, Essalmani R, Day R, Khatib AM, Seidah NG, Prat A. Proprotein convertase subtilisin/kexin type 9 deficiency reduces melanoma metastasis in liver. Neoplasia 2012;14:1122-31.
63. André P, Perlemuter G, Budkowska A, Bréchot C, Lotteau V. Hepatitis C virus particles and lipoprotein metabolism. Semin Liver Dis 2005;25:93-104.
64. Meredith LW, Wilson GK, Fletcher NF, McKeating JA. Hepatitis C virus entry: beyond receptors. Rev Med Virol 2012;22:182-93.
65. Labonté P, Begley S, Guévin C, Asselin MC, Nassoury N, Mayer G, et al. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology 2009;50:17-24.
66. Ikeda M, Abe K, Yamada M, Dansako H, Naka K, Kato N. Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology 2006;44:117-25.
67. Seidah NG. Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies. Curr Pharm Des 2013;19:3161-72.
68. Koren MJ, Giugliano RP, Raal FJ, Sullivan D, Bolognese M, Langslet G, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014;129:234-43.
69. Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. A 52-week placebocontrolled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809 -19.
70. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367:1891-900.