Skip to main content

Advertisement

Log in

Living the PCSK9 Adventure: from the Identification of a New Gene in Familial Hypercholesterolemia Towards a Potential New Class of Anticholesterol Drugs

  • Rare Diseases and Lipid Metabolism (JAG López, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

A decade after our discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in cholesterol metabolism through the identification of the first mutations leading to hypercholesterolemia, PCSK9 has become one of the most promising targets in cholesterol and cardiovascular diseases. This challenging work in the genetics of hypercholesterolemia paved the way for a plethora of studies around the world allowing the characterization of PCSK9, its expression, its impact on reducing the abundance of LDL receptor, and the identification of loss-of-function mutations in hypocholesterolemia. We highlight the different steps of this adventure and review the published clinical trials especially those with the anti-PCSK9 antibodies evolocumab (AMG 145) and alirocumab (SAR236553/REGN727), which are in phase III trials. The promising results in lowering LDL cholesterol levels raise hope that the PCSK9 adventure will lead, after the large and long-term ongoing phase III studies evaluating efficacy and safety, to a new anticholesterol pharmacological class.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Goldstein JL, Brown MS. Familial hypercholesterolemia: pathogenesis of a receptor disease. Johns Hopkins Med J. 1978;143:8–16.

    CAS  PubMed  Google Scholar 

  2. Innerarity TL, Weisgraber KH, Arnold KS, Mahley RW, Krauss RM, Vega GL, et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci U S A. 1987;84:6919–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Abifadel M, Varret M, Rabès J-P, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6.

  4. Varret M, Rabès JP, Saint-Jore B, Cenarro A, Marinoni JC, Civeira F, et al. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32. Am J Hum Genet. 1999;64:1378–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Hunt SC, Hopkins PN, Bulka K, McDermott MT, Thorne TL, Wardell BB, et al. Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Arterioscler Thromb Vasc Biol. 2000;20:1089–93.

    CAS  PubMed  Google Scholar 

  6. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Seidah NG, Prat A. Precursor convertases in the secretory pathway, cytosol and extracellular milieu. Essays Biochem. 2002;38:79–94.

    CAS  PubMed  Google Scholar 

  8. Naureckiene S, Ma L, Sreekumar K, Purandare U, Lo CF, Huang Y, et al. Functional characterization of Narc 1, a novel proteinase related to proteinase K. Arch Biochem Biophys. 2003;420:55–67.

    CAS  PubMed  Google Scholar 

  9. Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem. 2004;279:48865–75.

    CAS  PubMed  Google Scholar 

  10. 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.

    CAS  PubMed  Google Scholar 

  11. McNutt MC, Lagace TA, Horton JD. Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells. J Biol Chem. 2007;282:20799–803.

    CAS  PubMed  Google Scholar 

  12. 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 post-translational modifications. J Biol Chem. 2006;281:30561–72.

    CAS  PubMed  Google Scholar 

  13. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang D-W, Lagace TA, Garuti R, Zhao Z, McDonald 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.

    CAS  PubMed  Google Scholar 

  15. 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.

    CAS  PubMed  Google Scholar 

  16. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Berge KE, Ose L, Leren TP. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol. 2006;26:1094–100.

    CAS  PubMed  Google Scholar 

  19. 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.

    CAS  PubMed  Google Scholar 

  20. Abifadel M, Rabès J-P, Boileau C, Varret M. PCSK9, du gène à la protéine: un nouvel acteur dans l’homéostasie du cholestérol (PCSK9, from gene to protein: a new actor involved in cholesterol homeostasis). Med Sci. 2006;22:916–8.

    Google Scholar 

  21. Abifadel M, Rabès J-P, Boileau C, Varret M. Après le récepteur des LDL et l'apolipoprotéine B, l'hypercholestérolémie familiale révèle son troisième protagoniste : PCSK9 (After the LDL receptor and apolipoprotein B, autosomal dominant hypercholesterolemia reveals its third protagonist: PCSK9). Ann Endocrinol. 2007;68:138–46.

    CAS  Google Scholar 

  22. 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.

    CAS  PubMed  Google Scholar 

  23. Leren TP. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet. 2004;65:419–22.

    CAS  PubMed  Google Scholar 

  24. Sun X-M, Eden ER, Tosi I, Neuwirth CK, Wile D, Naoumova RP, et al. Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Hum Mol Genet. 2005;14:1161–9.

    CAS  PubMed  Google Scholar 

  25. Bourbon M, Alves AC, Medeiros AM, Silva S, Soutar AK. Familial hypercholesterolaemia in Portugal. Atherosclerosis. 2008;196:633–42.

    CAS  PubMed  Google Scholar 

  26. Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, et al. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat. 2005;26:497.

    PubMed  Google Scholar 

  27. Cameron J, Holla OL, Laerdahl JK, Kulseth MA, Ranheim T, Rognes T, et al. Characterization of novel mutations in the catalytic domain of the PCSK9 gene. J Intern Med. 2008;263:420–31.

    CAS  PubMed  Google Scholar 

  28. Homer VM, Marais AD, Charlton F, Laurie AD, Hurndell N, Scott R, et al. Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa. Atherosclerosis. 2008;196:659–66.

    CAS  PubMed  Google Scholar 

  29. Lin J, Wang L, Liu S, Wang X, Yong Q, Yang Y, et al. A novel mutation in proprotein convertase subtilisin/kexin type 9 gene leads to familial hypercholesterolemia in a Chinese family. Chin Med J (Engl). 2010;123:1133–8.

    CAS  Google Scholar 

  30. Abifadel M, Guerin M, Benjannet S, Rabès J-P, Le Goff W, Julia Z, et al. Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia. Atherosclerosis. 2012;223:394–400.

    CAS  PubMed  Google Scholar 

  31. Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A. 2004;101:7100–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci U S A. 2005;102:2069–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Cameron J, Holla ØL, Ranheim T, Kulseth MA, Berge KE, Leren TP. Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Hum Mol Genet. 2006;15:1551–8.

    CAS  PubMed  Google Scholar 

  34. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:161–5.

    CAS  PubMed  Google Scholar 

  35. Cohen JC, Boerwinkle E, Mosley Jr TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.

    CAS  PubMed  Google Scholar 

  36. Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet. 2006;78:410–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a southern African population. Atherosclerosis. 2007;193:445–8.

    CAS  PubMed  Google Scholar 

  38. Humphries SE, Neely RDG, Whittall RA, Troutt JS, Konrad RJ, Scartezini M, et al. Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9. Clin Chem. 2009;55:2153–61.

    CAS  PubMed  Google Scholar 

  39. Mayne J, Dewpura T, Raymond A, Bernier L, Cousins M, Ooi TC, et al. Novel loss-of-function PCSK9 variant is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture. Clin Chem. 2011;57:1415–23.

    CAS  PubMed  Google Scholar 

  40. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Cariou B, Ouguerram K, Zaïr Y, Guerois R, Langhi C, Kourimate S, et al. PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol. 2009;29:2191–7.

    CAS  PubMed  Google Scholar 

  42. Fasano T, Cefalù AB, Di Leo E, Noto D, Pollaccia D, Bocchi L, et al. A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arterioscler Thromb Vasc Biol. 2007;27:677–81.

    CAS  PubMed  Google Scholar 

  43. Miyake Y, Kimura R, Kokubo Y, Okayama A, Tomoike H, Yamamura T, et al. Genetic variants in PCSK9 in the Japanese population: rare genetic variants in PCSK9 might collectively contribute to plasma LDL cholesterol levels in the general population. Atherosclerosis. 2008;196:29–36.

    CAS  PubMed  Google Scholar 

  44. Abifadel M, Rabès J-P, 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.

    CAS  PubMed  Google Scholar 

  45. Polisecki E, Peter I, Robertson M, McMahon AD, Ford I, Packard C, et al. Genetic variation at the PCSK9 locus moderately lowers low-density lipoprotein cholesterol levels, but does not significantly lower vascular disease risk in an elderly population. Atherosclerosis. 2008;200:95–101.

    CAS  PubMed  Google Scholar 

  46. Chen SN, Ballantyne CM, Gotto Jr AM, Tan Y, Willerson JT, Marian AJ. A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. J Am Coll Cardiol. 2005;45:1611–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Norata GD, Garlaschelli K, Grigore L, Raselli S, Tramontana S, Meneghetti F, et al. Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles. Atherosclerosis. 2010;208:177–82.

    CAS  PubMed  Google Scholar 

  48. Evans D, Beil FU. The E670G SNP in the PCSK9 gene is associated with polygenic hypercholesterolemia in men but not in women. BMC Med Genet. 2006;7:66.

    PubMed  PubMed Central  Google Scholar 

  49. Hallman DM, Srinivasan SR, Chen W, Boerwinkle E, Berenson GS. Relation of PCSK9 mutations to serum low-density lipoprotein cholesterol in childhood and adulthood (from the Bogalusa Heart Study). Am J Cardiol. 2007;100:69–72.

    CAS  PubMed  Google Scholar 

  50. Abboud S, Karhunen PJ, Lütjohann D, Goebeler S, Luoto T, Friedrichs S, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a risk factor of large-vessel atherosclerosis stroke. PLoS One. 2007;2:e1043.

    PubMed  PubMed Central  Google Scholar 

  51. Scartezini M, Hubbart C, Whittall RA, Cooper JA, Neil AHW, Humphries SE. The PCSK9 gene R46L variant is associated with lower plasma lipid levels and cardiovascular risk in healthy U.K. men. Clin Sci Lond Engl 1979. 2007;113:435–41.

    CAS  Google Scholar 

  52. Kathiresan S. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N Engl J Med. 2008;358:2299–300.

    CAS  PubMed  Google Scholar 

  53. Folsom AR, Peacock JM, Boerwinkle E. Variation in PCSK9, low LDL cholesterol, and risk of peripheral arterial disease. Atherosclerosis. 2009;202:211–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Huang C-C, Fornage M, Lloyd-Jones DM, Wei GS, Boerwinkle E, Liu K. Longitudinal association of PCSK9 sequence variations with low-density lipoprotein cholesterol levels: the Coronary Artery Risk Development in Young Adults Study. Circ Cardiovasc Genet. 2009;2:354–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol. 2010;55:2833–42.

    CAS  PubMed  Google Scholar 

  56. Guella I, Asselta R, Ardissino D, Merlini PA, Peyvandi F, Kathiresan S, et al. Effects of PCSK9 genetic variants on plasma LDL cholesterol levels and risk of premature myocardial infarction in the Italian population. J Lipid Res. 2010;51:3342–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chernogubova E, Strawbridge R, Mahdessian H, Mälarstig A, Krapivner S, Gigante B, et al. Common and low-frequency genetic variants in the PCSK9 locus influence circulating PCSK9 levels. Arterioscler Thromb Vasc Biol. 2012;32:1526–34.

    CAS  PubMed  Google Scholar 

  58. Postmus I, Trompet S, de Craen AJM, Buckley BM, Ford I, Stott DJ, et al. PCSK9 SNP rs11591147 is associated with low cholesterol levels but not with cognitive performance or noncardiovascular clinical events in an elderly population. J Lipid Res. 2013;54:561–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Folsom AR, Peacock JM, Boerwinkle E. Sequence variation in proprotein convertase subtilisin/kexin type 9 serine protease gene, low LDL cholesterol, and cancer incidence. Cancer Epidemiol Biomark Prev. 2007;16:2455–8.

    CAS  Google Scholar 

  60. Brown MS, Goldstein JL. Biomedicine. Lowering LDL—not only how low, but how long? Science. 2006;311:1721–3.

    CAS  PubMed  Google Scholar 

  61. Myocardial Infarction Genetics Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet. 2009;41:334–41.

    PubMed Central  Google Scholar 

  62. Abifadel M, Rabès J-P, Jambart S, Halaby G, Gannagé-Yared M-H, Sarkis A, et al. The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene. Hum Mutat. 2009;30:E682–91.

    PubMed  Google Scholar 

  63. Pisciotta L, Priore Oliva C, Cefalù AB, Noto D, Bellocchio A, Fresa R, et al. Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia. Atherosclerosis. 2006;186:433–40.

    CAS  PubMed  Google Scholar 

  64. Abifadel M, Bernier L, Dubuc G, Nuel G, Rabès J-P, Bonneau J, et al. A PCSK9 variant and familial combined hyperlipidaemia. J Med Genet. 2008;45:780–6.

    CAS  PubMed  Google Scholar 

  65. Brouwers MCGJ, van Greevenbroek MMJ, Konrad RJ, Troutt JS, Schaper NC, Stehouwer CDA. Circulating PCSK9 is a strong determinant of plasma triacylglycerols and total cholesterol in homozygous carriers of apolipoprotein ε2. Clin Sci Lond Engl 1979. 2014;126:679–84.

    CAS  Google Scholar 

  66. Brouwers MCGJ, Konrad RJ, van Himbergen TM, Isaacs A, Otokozawa S, Troutt JS, et al. Plasma proprotein convertase subtilisin kexin type 9 levels are related to markers of cholesterol synthesis in familial combined hyperlipidemia. Nutr Metab Cardiovasc Dis. 2013;23:1115–21.

    CAS  PubMed  Google Scholar 

  67. 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.

    CAS  PubMed  Google Scholar 

  68. Herbert B, Patel D, Waddington SN, Eden ER, McAleenan A, Sun X-M, et al. Increased secretion of lipoproteins in transgenic mice expressing human D374Y PCSK9 under physiological genetic control. Arterioscler Thromb Vasc Biol. 2010;30:1333–9.

    CAS  PubMed  Google Scholar 

  69. Sun H, Samarghandi A, Zhang N, Yao Z, Xiong M, Teng B-B. 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.

    CAS  PubMed  Google Scholar 

  70. Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res. 2003;44:2109–19.

    CAS  PubMed  Google Scholar 

  71. 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.

    CAS  PubMed  Google Scholar 

  72. Persson L, Gälman C, Angelin B, Rudling M. Importance of proprotein convertase subtilisin/kexin type 9 in the hormonal and dietary regulation of rat liver low-density lipoprotein receptors. Endocrinology. 2009;150:1140–6.

    CAS  PubMed  Google Scholar 

  73. Langhi C, Le May C, Kourimate S, Caron S, Staels B, Krempf M, et al. Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. FEBS Lett. 2008;582:949–55.

    CAS  PubMed  Google Scholar 

  74. Konrad RJ, Troutt JS, Cao G. Effects of currently prescribed LDL-C-lowering drugs on PCSK9 and implications for the next generation of LDL-C-lowering agents. Lipids Health Dis. 2011;10:38.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Davignon J, Dubuc G. Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans Am Clin Climatol Assoc. 2009;120:163–73.

    PubMed  PubMed Central  Google Scholar 

  77. 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.

    PubMed  PubMed Central  Google Scholar 

  78. Kourimate S, Le May C, Langhi C, Jarnoux AL, Ouguerram K, Zaïr Y, et al. Dual mechanisms for the fibrate-mediated repression of proprotein convertase subtilisin/kexin type 9. J Biol Chem. 2008;283:9666–73.

    CAS  PubMed  Google Scholar 

  79. Lambert G, Ancellin N, Charlton F, Comas D, Pilot J, Keech A, et al. Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment. Clin Chem. 2008;54:1038–45.

    CAS  PubMed  Google Scholar 

  80. Noguchi T, Kobayashi J, Yagi K, Nohara A, Yamaaki N, Sugihara M, et al. Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: results from a crossover study. Atherosclerosis. 2011;217:165–70.

    CAS  PubMed  Google Scholar 

  81. Troutt JS, Alborn WE, Cao G, Konrad RJ. Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels. J Lipid Res. 2010;51:345–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Alborn WE, Cao G, Careskey HE, Qian Y-W, Subramaniam DR, Davies J, et al. Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol. Clin Chem. 2007;53:1814–9.

    CAS  PubMed  Google Scholar 

  84. Huijgen R, Fouchier SW, Denoun M, Hutten BA, Vissers MN, Lambert G, et al. Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia. J Lipid Res. 2012;53:979–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Steinberg D, Witztum JL. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels. Proc Natl Acad Sci U S A. 2009;106:9546–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Bjermo H, Iggman D, Kullberg J, Dahlman I, Johansson L, Persson L, et al. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Am J Clin Nutr. 2012;95:1003–12.

    CAS  PubMed  Google Scholar 

  87. Richard C, Couture P, Desroches S, Benjannet S, Seidah NG, Lichtenstein AH, et al. 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.

    CAS  PubMed  Google Scholar 

  88. 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. 2012;32:810–4.

    CAS  PubMed  Google Scholar 

  89. Cariou B, Le Bras M, Langhi C, Le May C, Guyomarc’h-Delasalle B, Krempf M, et al. Association between plasma PCSK9 and gamma-glutamyl transferase levels in diabetic patients. Atherosclerosis. 2010;211:700–2.

    CAS  PubMed  Google Scholar 

  90. Lee CJ, Lee Y-H, Park SW, Kim KJ, Park S, Youn J-C, et al. Association of serum proprotein convertase subtilisin/kexin type 9 with carotid intima media thickness in hypertensive subjects. Metabolism. 2013;62:845–50.

    CAS  PubMed  Google Scholar 

  91. Constantinides A, Kappelle PJWH, Lambert G, Dullaart RPF. Plasma lipoprotein-associated phospholipase A2 is inversely correlated with proprotein convertase subtilisin-kexin type 9. Arch Med Res. 2012;43:11–4.

    CAS  PubMed  Google Scholar 

  92. Kwakernaak AJ, Lambert G, Slagman MCJ, Waanders F, Laverman GD, Petrides F, et al. Proprotein convertase subtilisin-kexin type 9 is elevated in proteinuric subjects: relationship with lipoprotein response to antiproteinuric treatment. Atherosclerosis. 2013;226:459–65.

    CAS  PubMed  Google Scholar 

  93. Melone M, Wilsie L, Palyha O, Strack A, Rashid S. Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. J Am Coll Cardiol. 2012;59:1697–705.

    CAS  PubMed  Google Scholar 

  94. Kwakernaak AJ, Lambert G, Dullaart RPF. Relationship of proprotein convertase subtilisin-kexin type 9 levels with resistin in lean and obese subjects. Clin Biochem. 2012;45:1522–4.

    CAS  PubMed  Google Scholar 

  95. Abifadel M, Pakradouni J, Collin M, Samson-Bouma M-E, Varret M, Rabès J-P, et al. Strategies for proprotein convertase subtilisin kexin 9 modulation: a perspective on recent patents. Expert Opin Ther Pat. 2010;20:1547–71.

    CAS  PubMed  Google Scholar 

  96. Stein EA, Kasichayanula S, Turner T, Kranz T, Arumugam U, Biernat L, et al. LDL Cholesterol reduction with BMS-962476, an adnectin inhibitor of PCSK9: results of a single ascending dose study. J Am Coll Cardiol. 2014;63(12 Suppl):A172. doi:10.1016/S0735-1097(14)61372-3.

    Google Scholar 

  97. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet. 2014;383:60–8. This is a report of a phase I trial using RNA interference to reduce PCSK9 levels.

    CAS  PubMed  Google Scholar 

  98. Tingley W, Luca D, Leabman M, Budha N, Kahn R, Baruch A, et al. Effects of RG7652, a fully human mAb against proprotein convertase subtilisin/kexin type 9, on LDL-c: a Phase I, randomised, double-blind, placebo-controlled, single- and multiple-dose study. Eur Heart J. 2013;34:P4183.

    Google Scholar 

  99. Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang E, Plowchalk D, et al. Efficacy and safety of bococizumab (RN316/PF-04950615), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 in statin-treated hypercholesterolemic subjects: results from a randomized, placebo-controlled, dose-ranging study (NCT: 01592240). J Am Coll Cardiol. 2014;63(12 Suppl):A1374. doi:10.1016/S0735-1097(14)61374-7.

    Google Scholar 

  100. Dias CS, Shaywitz AJ, Wasserman SM, Smith BP, Gao B, Stolman DS, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012;60:1888–98.

    CAS  PubMed  Google Scholar 

  101. Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation. 2012;126:2408–17.

    CAS  PubMed  Google Scholar 

  102. Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380:1995–2006.

    CAS  PubMed  Google Scholar 

  103. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308:2497–506.

    CAS  PubMed  Google Scholar 

  104. Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380:2007–17.

    CAS  PubMed  Google Scholar 

  105. Kohli P, Desai NR, Giugliano RP, Kim JB, Somaratne R, Huang F, et al. Design and rationale of the LAPLACE-TIMI 57 trial: a phase II, double-blind, placebo-controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy. Clin Cardiol. 2012;35:385–91.

    PubMed  Google Scholar 

  106. 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.

    CAS  PubMed  Google Scholar 

  107. Mearns BM. Dyslipidaemia: 1-year results from OSLER trial of anti-PCSK9 monoclonal antibody evolocumab. Nat Rev Cardiol. 2014;11:63.

    PubMed  Google Scholar 

  108. Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation. 2013;128:2113–20.

    CAS  PubMed  Google Scholar 

  109. Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809–19. This article reviews the DESCARTES phase III trial investigating the effect of AMG 145 (evolocumab) given for 52 weeks in patients with hyperlipidemia.

    CAS  PubMed  Google Scholar 

  110. Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2531–40.

    CAS  PubMed  Google Scholar 

  111. Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541–8.

    CAS  PubMed  Google Scholar 

  112. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108–18. This article describes the results of three phase I trials using REGN727 (alirocumab) in single-dose and multiple-doses studies.

    CAS  PubMed  Google Scholar 

  113. Crunkhorn S. Trial watch: PCSK9 antibody reduces LDL cholesterol. Nat Rev Drug Discov. 2012;11:11.

    CAS  PubMed  Google Scholar 

  114. 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.

    CAS  PubMed  Google Scholar 

  115. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand A-C, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59:2344–53.

    CAS  PubMed  Google Scholar 

  116. Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci U S A. 2008;105:11915–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Liu M, Wu G, Baysarowich J, Kavana M, Addona GH, Bierilo KK, et al. PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain. J Lipid Res. 2010;51:2611–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. DeVay RM, Shelton DL, Liang H. Characterization of proprotein convertase subtilisin/kexin type 9 (PCSK9) trafficking reveals a novel lysosomal targeting mechanism via amyloid precursor-like protein 2 (APLP2). J Biol Chem. 2013;288:10805–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Shibata N, Ohnuma T, Higashi S, Higashi M, Usui C, Ohkubo T, et al. No genetic association between PCSK9 polymorphisms and Alzheimer’s disease and plasma cholesterol level in Japanese patients. Psychiatr Genet. 2005;15:239.

    PubMed  Google Scholar 

  121. Rousselet E, Marcinkiewicz J, Kriz J, Zhou A, Hatten ME, Prat A, et al. PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke. J Lipid Res. 2011;52:1383–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Roubtsova A, Munkonda MN, Awan Z, Marcinkiewicz J, Chamberland A, Lazure C, et al. Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler Thromb Vasc Biol. 2011;31:785–91.

    CAS  PubMed  Google Scholar 

  123. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Sharotri V, Collier DM, Olson DR, Zhou R, Snyder PM. Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). J Biol Chem. 2012;287:19266–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Seidah NG, Poirier S, Denis M, Parker R, Miao B, Mapelli C, et al. Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. PLoS One. 2012;7:e41865.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Labonté P, Begley S, Guévin C, Asselin M-C, Nassoury N, Mayer G, et al. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology. 2009;50:17–24.

    PubMed  Google Scholar 

  127. 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.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from Fondation-Leducq (FLQ # 13 CVD 03) through the Transatlantic Networks of Excellence in Cardiovascular Research program (“The function and regulation of PCSK9: a novel modulator of LDLR activity”); Institut National de la Santé et de la Recherche Médicale (INSERM); Conseil de la Recherche de l’Université Saint-Joseph (Beirut, Lebanon), and Conseil National de la Recherche Scientifique Libanais.

Compliance with Ethics Guidelines

Conflict of Interest

Marianne Abifadel is member of the advisory board of Amgen and is involved in anti-PCSK9 studies and trials with Amgen and with Regeneron and Sanofi. Jean-Pierre Rabès and Catherine Boileau are involoved in anti-PCSK9 studies with Regeneron and Sanofi.

Sandy Elbitar, Petra El Khoury, Youmna Ghaleb, Mélody Chémaly, Marie-Line Moussalli, and Mathilde Varret declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marianne Abifadel.

Additional information

This article is part of the Topical Collection on Rare Diseases and Lipid Metabolism

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abifadel, M., Elbitar, S., El Khoury, P. et al. Living the PCSK9 Adventure: from the Identification of a New Gene in Familial Hypercholesterolemia Towards a Potential New Class of Anticholesterol Drugs. Curr Atheroscler Rep 16, 439 (2014). https://doi.org/10.1007/s11883-014-0439-8

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11883-014-0439-8

Keywords

Navigation