Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9)

Basic Research in Cardiology

Volumn 110, Issue 2, 2015, Pages

  Schulz, Rainer ^a   Schlüter, Klaus Dieter ^a   Laufs, Ulrich ^b  

^a JUSTUS LIEBIG UNIVERSITY   (Germany)

^b SAARLAND UNIVERSITY   (Germany)

Author keywords

Cardiovascular disease; Cholesterol; Heart; PCSK9

Indexed keywords

ALIROCUMAB; ALN PCS; ATORVASTATIN; BERBERINE; BMS 962476; BOCOCIZUMAB; CHOLESTEROL ESTER TRANSFER PROTEIN INHIBITOR; EPITHELIAL SODIUM CHANNEL; EVOLOCUMAB; EZETIMIBE; FIBRIC ACID DERIVATIVE; GLITAZONE DERIVATIVE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INDUCIBLE DEGRADER OF LOW DENSITY LIPOPROTEIN RECEPTOR; LGT 209; LIPOPROTEIN A; LOW DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN RECEPTOR; LY 3015014; MEVALONIC ACID; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 INHIBITOR; RAPAMYCIN; REGN 7272; RESISTIN; RG 7652; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; PCSK9 PROTEIN, HUMAN;

ACUTE HEART INFARCTION; ANTIGEN BINDING; ARTERIAL WALL THICKNESS; ATHEROSCLEROSIS; BRAIN; CARDIOVASCULAR RISK; CHOLESTEROL TRANSPORT; CORONARY ARTERY DISEASE; DRUG MEGADOSE; ENDOSOME; ENZYME ACTIVITY; ENZYME BLOOD LEVEL; ENZYME INHIBITION; FAMILIAL HYPERCHOLESTEROLEMIA; GAIN OF FUNCTION MUTATION; GENE CONTROL; GENE EXPRESSION; HUMAN; HYPERCHOLESTEROLEMIA; INFLAMMATION; INNATE IMMUNITY; INTRAABDOMINAL FAT; LIPID ABSORPTION; LIPID HOMEOSTASIS; LOSS OF FUNCTION MUTATION; LYSOSOME; NEPHROTIC SYNDROME; NONHUMAN; PANCREAS ISLET BETA CELL; PATHOGENESIS; PCSK9 GENE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; REVIEW; ANIMAL; CARDIOVASCULAR DISEASE; HOMEOSTASIS; PATHOPHYSIOLOGY; PHYSIOLOGY;

ANIMALS; CARDIOVASCULAR DISEASES; HOMEOSTASIS; HUMANS; PROPROTEIN CONVERTASES; SERINE ENDOPEPTIDASES;

EID: 84921417221     PISSN: 03008428     EISSN: 14351803     Source Type: Journal    
DOI: 10.1007/s00395-015-0463-z     Document Type: Review

References (181)

1. Abifadel M, Rabes JP, Boileau C, Varret M (2007) After the LDL receptor and apolipoprotein B, autosomal dominant hypercholesterolemia reveals its third protagonist: PCSK9. Ann Endocrinol (Paris) 68:138–146. doi:10.1016/j.ando.2007.02.002
2. Ai D, Chen C, Han S, Ganda A, Murphy AJ, Haeusler R, Thorp E, Accili D, Horton JD, Tall AR (2012) Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. J Clin Invest 122:1262–1270. doi:10.1172/JCI61919
3. Al-Mashhadi RH, Sorensen CB, Kragh PM, Christoffersen C, Mortensen MB, Tolbod LP, Thim T, Du Y, Li J, Liu Y, Moldt B, Schmidt M, Vajta G, Larsen T, Purup S, Bolund L, Nielsen LB, Callesen H, Falk E, Mikkelsen JG, Bentzon JF (2013) Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Sci Transl Med 5:166ra1. doi:10.1126/scitranslmed.3004853
4. Alborn WE, Cao G, Careskey HE, Qian YW, Subramaniam DR, Davies J, Conner EM, Konrad RJ (2007) Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol. Clin Chem 53:1814–1819. doi:10.1373/clinchem.2007.091280
5. Almontashiri NA, Vilmundarson RO, Ghasemzadeh N, Dandona S, Roberts R, Quyyumi AA, Chen HH, Stewart AF (2014) Plasma PCSK9 levels are elevated with acute myocardial infarction in two independent retrospective angiographic studies. PLoS One 9:e106294. doi:10.1371/journal.pone.0106294
6. Araki S, Suga S, Miyake F, Ichikawa S, Kinjo T, Yamamoto Y, Kusuhara K (2014) Circulating PCSK9 levels correlate with the serum LDL cholesterol level in newborn infants. Early Hum Dev 90:607–611. doi:10.1016/j.earlhumdev.2014.07.013
7. Ason B, Tep S, Davis HR Jr, Xu Y, Tetzloff G, Galinski B, Soriano F, Dubinina N, Zhu L, Stefanni A, Wong KK, Tadin-Strapps M, Bartz SR, Hubbard B, Ranalletta M, Sachs AB, Flanagan WM, Strack A, Kuklin NA (2011) Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9. J Lipid Res 52:679–687. doi:10.1194/jlr.M013664
8. Ason B, van der Hoorn JW, Chan J, Lee E, Pieterman EJ, Nguyen KK, Di M, Shetterly S, Tang J, Yeh WC, Schwarz M, Jukema JW, Scott R, Wasserman SM, Princen HM, Jackson S (2014) PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE. J Lipid Res 55:2370–2379. doi:10.1194/jlr.M053207
9. Awan Z, Dubuc G, Faraj M, Dufour R, Seidah NG, Davignon J, Rabasa-Lhoret R, Baass A (2014) The effect of insulin on circulating PCSK9 in postmenopausal obese women. Clin Biochem 47:1033–1039. doi:10.1016/j.clinbiochem.2014.03.022
10. Awan Z, Seidah NG, MacFadyen JG, Benjannet S, Chasman DI, Ridker PM, Genest J (2012) Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clin Chem 58:183–189. doi:10.1373/clinchem.2011.172932
11. Baass A, Dubuc G, Tremblay M, Delvin EE, O’Loughlin J, Levy E, Davignon J, Lambert M (2009) Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents. Clin Chem 55:1637–1645. doi:10.1373/clinchem.2009.126987
12. Beaudoin M, Lo KS, N’Diaye A, Rivas MA, Dube MP, Laplante N, Phillips MS, Rioux JD, Tardif JC, Lettre G (2012) Pooled DNA resequencing of 68 myocardial infarction candidate genes in French canadians. Circ Cardiovasc Genet 5:547–554. doi:10.1161/CIRCGENETICS.112.963165
13. Benjannet S, Hamelin J, Chretien M, Seidah NG (2012) Loss- and gain-of-function PCSK9 variants: cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation. J Biol Chem 287:33745–33755. doi:10.1074/jbc.M112.399725
14. Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, Asselin MC, Hamelin J, Varret M, Allard D, Trillard M, Abifadel M, Tebon A, Attie AD, Rader DJ, Boileau C, Brissette L, Chretien M, Prat A, Seidah NG (2004) NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem 279:48865–48875. doi:10.1074/jbc.M409699200
15. Benjannet S, Rhainds D, Hamelin J, Nassoury N, Seidah NG (2006) 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 281:30561–30572. doi:10.1074/jbc.M606495200
16. Benjannet S, Saavedra YG, Hamelin J, Asselin MC, Essalmani R, Pasquato A, Lemaire P, Duke G, Miao B, Duclos F, Parker R, Mayer G, Seidah NG (2010) Effects of the prosegment and pH on the activity of PCSK9: evidence for additional processing events. J Biol Chem 285:40965–40978. doi:10.1074/jbc.M110.154815
17. Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A (2010) PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol 55:2833–2842. doi:10.1016/j.jacc.2010.02.044
18. Berthold HK, Seidah NG, Benjannet S, Gouni-Berthold I (2013) Evidence from a randomized trial that simvastatin, but not ezetimibe, upregulates circulating PCSK9 levels. PLoS One 8:e60095. doi:10.1371/journal.pone.0060095
19. Bingham B, Shen R, Kotnis S, Lo CF, Ozenberger BA, Ghosh N, Kennedy JD, Jacobsen JS, Grenier JM, DiStefano PS, Chiang LW, Wood A (2006) Proapoptotic effects of NARC 1 (=PCSK9), the gene encoding a novel serine proteinase. Cytometry A 69:1123–1131. doi:10.1002/cyto.a.20346
20. Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, Ceska R, Roth E, Koren MJ, Ballantyne CM, Monsalvo ML, Tsirtsonis K, Kim JB, Scott R, Wasserman SM, Stein EA (2014) A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 370:1809–1819. doi:10.1056/NEJMoa1316222
21. Bottomley MJ, Cirillo A, Orsatti L, Ruggeri L, Fisher TS, Santoro JC, Cummings RT, Cubbon RM, Lo SP, Calzetta A, Noto A, Baysarowich J, Mattu M, Talamo F, De FR, Sparrow CP, Sitlani A, Carfi A (2009) Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants. J Biol Chem 284:1313–1323. doi:10.1074/jbc.M808363200
22. Brouwers MC, Troutt JS, van Greevenbroek MM, Ferreira I, Feskens EJ, van der Kallen CJ, Schaper NC, Schalkwijk CG, Konrad RJ, Stehouwer CD (2011) Plasma proprotein convertase subtilisin kexin type 9 is not altered in subjects with impaired glucose metabolism and type 2 diabetes mellitus, but its relationship with non-HDL cholesterol and apolipoprotein B may be modified by type 2 diabetes mellitus: the CODAM study. Atherosclerosis 217:263–267. doi:10.1016/j.atherosclerosis.2011.03.023
23. Browning JD, Horton JD (2010) Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9 and cholesterol biosynthesis in humans. J Lipid Res 51:3359–3363. doi:10.1194/jlr.P009860
24. Cameron J, Bogsrud MP, Tveten K, Strom TB, Holven K, Berge KE, Leren TP (2012) Serum levels of proprotein convertase subtilisin/kexin type 9 in subjects with familial hypercholesterolemia indicate that proprotein convertase subtilisin/kexin type 9 is cleared from plasma by low-density lipoprotein receptor-independent pathways. Transl Res 160:125–130. doi:10.1016/j.trsl.2012.01.010
25. Cameron J, Holla OL, Laerdahl JK, Kulseth MA, Berge KE, Leren TP (2009) Mutation S462P in the PCSK9 gene reduces secretion of mutant PCSK9 without affecting the autocatalytic cleavage. Atherosclerosis 203:161–165. doi:10.1016/j.atherosclerosis.2008.10.007
26. Cameron J, Ranheim T, Kulseth MA, Leren TP, Berge KE (2008) Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis 201:266–273. doi:10.1016/j.atherosclerosis.2008.02.004
27. Canuel M, Sun X, Asselin MC, Paramithiotis E, Prat A, Seidah NG (2013) Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1). PLoS One 8:e64145. doi:10.1371/journal.pone.0064145
28. Cariou B, Langhi C, Le BM, Bortolotti M, Le KA, Theytaz F, Le MC, Guyomarc’h-Delasalle B, Zair Y, Kreis R, Boesch C, Krempf M, Tappy L, Costet P (2013) Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets. Nutr Metab (Lond) 10:4. doi:10.1186/1743-7075-10-4
29. Cariou B, Le BM, Langhi C, Le MC, Guyomarc’h-Delasalle B, Krempf M, Costet P (2010) Association between plasma PCSK9 and gamma-glutamyl transferase levels in diabetic patients. Atherosclerosis 211:700–702. doi:10.1016/j.atherosclerosis.2010.04.015
30. Chan JC, Piper DE, Cao Q, Liu D, King C, Wang W, Tang J, Liu Q, Higbee J, Xia Z, Di Y, Shetterly S, Arimura Z, Salomonis H, Romanow WG, Thibault ST, Zhang R, Cao P, Yang XP, Yu T, Lu M, Retter MW, Kwon G, Henne K, Pan O, Tsai MM, Fuchslocher B, Yang E, Zhou L, Lee KJ, Daris M, Sheng J, Wang Y, Shen WD, Yeh WC, Emery M, Walker NP, Shan B, Schwarz M, Jackson SM (2009) A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci USA 106:9820–9825. doi:10.1073/pnas.0903849106
31. Chen XW, Wang H, Bajaj K, Zhang P, Meng ZX, Ma D, Bai Y, Liu HH, Adams E, Baines A, Yu G, Sartor MA, Zhang B, Yi Z, Lin J, Young SG, Schekman R, Ginsburg D (2013) SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion. Elife 2:e00444. doi:10.7554/eLife.00444;00444
32. Chen Y, Wang H, Yu L, Yu X, Qian YW, Cao G, Wang J (2011) Role of ubiquitination in PCSK9-mediated low-density lipoprotein receptor degradation. Biochem Biophys Res Commun 415:515–518. doi:10.1016/j.bbrc.2011.10.110
33. Chen YQ, Troutt JS, Konrad RJ (2014) PCSK9 is present in human cerebrospinal fluid and is maintained at remarkably constant concentrations throughout the course of the day. Lipids 49:445–455. doi:10.1007/s11745-014-3895-6
34. Chernogubova E, Strawbridge R, Mahdessian H, Malarstig A, Krapivner S, Gigante B, Hellenius ML, de FU, Franco-Cereceda A, Syvanen AC, Troutt JS, Konrad RJ, Eriksson P, Hamsten A, van ‘t Hooft FM (2012) Common and low-frequency genetic variants in the PCSK9 locus influence circulating PCSK9 levels. Arterioscler Thromb Vasc Biol 32:1526–1534. doi:10.1161/ATVBAHA.111.240549
35. Cho L, Rocco M, Colquhoun D, Sullivan D, Rosenson RS, Dent R, Xue A, Scott R, Wasserman SM, Stroes E (2014) Design and rationale of the GAUSS-2 study trial: a double-blind, ezetimibe-controlled phase 3 study of the efficacy and tolerability of evolocumab (AMG 145) in subjects with hypercholesterolemia who are intolerant of statin therapy. Clin Cardiol 37:131–139. doi:10.1002/clc.22248
36. Chorba JS, Shokat KM (2014) The proprotein convertase subtilisin/kexin type 9 (PCSK9) active site and cleavage sequence differentially regulate protein secretion from proteolysis. J Biol Chem 289:29030–29043. doi:10.1074/jbc.M114.594861
37. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354:1264–1272. doi:10.1056/NEJMoa054013
38. Colhoun HM, Robinson JG, Farnier M, Cariou B, Blom D, Kereiakes DJ, Lorenzato C, Pordy R, Chaudhari U (2014) Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials. BMC Cardiovasc Disord 14:121. doi:10.1186/1471-2261-14-121
39. Costet P, Cariou B, Lambert G, Lalanne F, Lardeux B, Jarnoux AL, Grefhorst A, Staels B, Krempf M (2006) Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. J Biol Chem 281:6211–6218. doi:10.1074/jbc.M508582200
40. Costet P, Hoffmann MM, Cariou B, Guyomarc’h DB, Konrad T, Winkler K (2010) Plasma PCSK9 is increased by fenofibrate and atorvastatin in a non-additive fashion in diabetic patients. Atherosclerosis 212:246–251. doi:10.1016/j.atherosclerosis.2010.05.027
41. Denis M, Marcinkiewicz J, Zaid A, Gauthier D, Poirier S, Lazure C, Seidah NG, Prat A (2012) Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 125:894–901. doi:10.1161/CIRCULATIONAHA.111.057406
42. Desai NR, Giugliano RP, Zhou J, Kohli P, Somaratne R, Hoffman E, Liu T, Scott R, Wasserman SM, Sabatine MS (2014) AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of national cholesterol education program-adult treatment panel III low-density lipoprotein cholesterol goals among high-risk patients: an analysis from the LAPLACE-TIMI 57 trial (LDL-C assessment with PCSK9 monoclonal antibody inhibition combined with statin thErapy-thrombolysis in myocardial infarction 57). J Am Coll Cardiol 63:430–433. doi:10.1016/j.jacc.2013.09.048
43. Desai NR, Kohli P, Giugliano RP, O’Donoghue ML, Somaratne R, Zhou J, Hoffman EB, Huang F, Rogers WJ, Wasserman SM, Scott R, Sabatine MS (2013) AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial. Circulation 128:962–969. doi:10.1161/CIRCULATIONAHA.113.001969
44. DeVay RM, Shelton DL, Liang H (2013) 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 288:10805–10818. doi:10.1074/jbc.M113.453373
45. Dewpura T, Raymond A, Hamelin J, Seidah NG, Mbikay M, Chretien M, Mayne J (2008) PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans. FEBS J 275:3480–3493. doi:10.1111/j.1742-4658.2008.06495.x
46. Dias CS, Shaywitz AJ, Wasserman SM, Smith BP, Gao B, Stolman DS, Crispino CP, Smirnakis KV, Emery MG, Colbert A, Gibbs JP, Retter MW, Cooke BP, Uy ST, Matson M, Stein EA (2012) 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 60:1888–1898. doi:10.1016/j.jacc.2012.08.986
47. Dong B, Wu M, Cao A, Li H, Liu J (2011) Suppression of Idol expression is an additional mechanism underlying statin-induced up-regulation of hepatic LDL receptor expression. Int J Mol Med 27:103–110. doi:10.3892/ijmm.2010.559
48. Dong B, Wu M, Li H, Kraemer FB, Adeli K, Seidah NG, Park SW, Liu J (2010) Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. J Lipid Res 51:1486–1495. doi:10.1194/jlr.M003566
49. Du F, Hui Y, Zhang M, Linton MF, Fazio S, Fan D (2011) Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. J Biol Chem 286:43054–43061. doi:10.1074/jbc.M111.273474
50. Duan Y, Chen Y, Hu W, Li X, Yang X, Zhou X, Yin Z, Kong D, Yao Z, Hajjar DP, Liu L, Liu Q, Han J (2012) Peroxisome Proliferator-activated receptor gamma activation by ligands and dephosphorylation induces proprotein convertase subtilisin kexin type 9 and low density lipoprotein receptor expression. J Biol Chem 287:23667–23677. doi:10.1074/jbc.M112.350181
51. Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A (2004) Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 24:1454–1459. doi:10.1161/01.ATV.0000134621.14315.43
52. Essalmani R, Susan-Resiga D, Chamberland A, Abifadel M, Creemers JW, Boileau C, Seidah NG, Prat A (2011) In vivo evidence that furin from hepatocytes inactivates PCSK9. J Biol Chem 286:4257–4263. doi:10.1074/jbc.M110.192104
53. Fan D, Yancey PG, Qiu S, Ding L, Weeber EJ, Linton MF, Fazio S (2008) Self-association of human PCSK9 correlates with its LDLR-degrading activity. Biochemistry 47:1631–1639. doi:10.1021/bi7016359
54. Feingold KR, Moser AH, Shigenaga JK, Patzek SM, Grunfeld C (2008) Inflammation stimulates the expression of PCSK9. Biochem Biophys Res Commun 374:341–344. doi:10.1016/j.bbrc.2008.07.023
55. Fisher TS, Lo SP, Pandit S, Mattu M, Santoro JC, Wisniewski D, Cummings RT, Calzetta A, Cubbon RM, Fischer PA, Tarachandani A, De FR, Wright SD, Sparrow CP, Carfi A, Sitlani A (2007) Effects of pH and low density lipoprotein (LDL) on PCSK9-dependent LDL receptor regulation. J Biol Chem 282:20502–20512. doi:10.1074/jbc.M701634200
56. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, Hutabarat RM, Clausen VA, Karsten V, Cehelsky J, Nochur SV, Kotelianski V, Horton J, Mant T, Chiesa J, Ritter J, Munisamy M, Vaishnaw AK, Gollob JA, Simon A (2014) 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 383:60–68. doi:10.1016/S0140-6736(13)61914-5
57. Folsom AR, Peacock JM, Boerwinkle E (2007) Sequence variation in proprotein convertase subtilisin/kexin type 9 serine protease gene, low LDL cholesterol, and cancer incidence. Cancer Epidemiol Biomarkers Prev 16:2455–2458. doi:10.1158/1055-9965.EPI-07-0502
58. Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, Gamba-Vitalo C, Hadwiger P, Jayaraman M, John M, Jayaprakash KN, Maier M, Nechev L, Rajeev KG, Read T, Rohl I, Soutschek J, Tan P, Wong J, Wang G, Zimmermann T, de FA, Vornlocher HP, Langer R, Anderson DG, Manoharan M, Koteliansky V, Horton JD, Fitzgerald K (2008) Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci USA 105:11915–11920. doi:10.1073/pnas.0805434105
59. Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, Gipe D, Du Y, Ferrand AC, Ginsberg HN, Stein EA (2014) Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol 114:711–715. doi:10.1016/j.amjcard.2014.05.060
60. Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F, Liu T, Mohanavelu S, Hoffman EB, McDonald ST, Abrahamsen TE, Wasserman SM, Scott R, Sabatine MS (2012) 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 380:2007–2017. doi:10.1016/S0140-6736(12)61770-X
61. Grozdanov PN, Petkov PM, Karagyozov LK, Dabeva MD (2006) Expression and localization of PCSK9 in rat hepatic cells. Biochem Cell Biol 84:80–92. doi:10.1139/o05-155
62. Gu HM, Adijiang A, Mah M, Zhang DW (2013) Characterization of the role of EGF-A of low density lipoprotein receptor in PCSK9 binding. J Lipid Res 54:3345–3357. doi:10.1194/jlr.M041129
63. Guella I, Asselta R, Ardissino D, Merlini PA, Peyvandi F, Kathiresan S, Mannucci PM, Tubaro M, Duga S (2010) Effects of PCSK9 genetic variants on plasma LDL cholesterol levels and risk of premature myocardial infarction in the Italian population. J Lipid Res 51:3342–3349. doi:10.1194/jlr.M010009
64. Guo YL, Liu J, Xu RX, Zhu CG, Wu NQ, Jiang LX, Li JJ (2013) Short-term impact of low-dose atorvastatin on serum proprotein convertase subtilisin/kexin type 9. Clin Drug Investig 33:877–883. doi:10.1007/s40261-013-0129-2
65. Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Orum H, Elmen J, Seidah NG, Straarup EM (2010) A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PLoS One 5:e10682. doi:10.1371/journal.pone.0010682
66. Gustafsen C, Kjolby M, Nyegaard M, Mattheisen M, Lundhede J, Buttenschon H, Mors O, Bentzon JF, Madsen P, Nykjaer A, Glerup S (2014) The hypercholesterolemia-risk gene SORT1 facilitates PCSK9 secretion. Cell Metab 19:310–318. doi:10.1016/j.cmet.2013.12.006
67. Han B, Eacho PI, Knierman MD, Troutt JS, Konrad RJ, Yu X, Schroeder KM (2014) Isolation and characterization of the circulating truncated form of PCSK9. J Lipid Res 55:1505–1514. doi:10.1194/jlr.M049346
68. Hentze H, Jensen KK, Chia SM, Johns DG, Shaw RJ, Davis HR Jr, Shih SJ, Wong KK (2013) Inverse relationship between LDL cholesterol and PCSK9 plasma levels in dyslipidemic cynomolgus monkeys: effects of LDL lowering by ezetimibe in the absence of statins. Atherosclerosis 231:84–90. doi:10.1016/j.atherosclerosis.2013.08.028
69. Hirayama A, Honarpour N, Yoshida M, Yamashita S, Huang F, Wasserman SM, Teramoto T (2014) Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk–primary results from the phase 2 YUKAWA study. Circ J 78:1073–1082 (DN/JST.JSTAGE/circj/CJ-14-0130 [pii])
70. Holla OL, Cameron J, Tveten K, Strom TB, Berge KE, Laerdahl JK, Leren TP (2011) Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors. J Lipid Res 52:1787–1794. doi:10.1194/jlr.M018093
71. Holla OL, Laerdahl JK, Strom TB, Tveten K, Cameron J, Berge KE, Leren TP (2011) Removal of acidic residues of the prodomain of PCSK9 increases its activity towards the LDL receptor. Biochem Biophys Res Commun 406:234–238. doi:10.1016/j.bbrc.2011.02.023
72. Homer VM, Marais AD, Charlton F, Laurie AD, Hurndell N, Scott R, Mangili F, Sullivan DR, Barter PJ, Rye KA, George PM, Lambert G (2008) Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa. Atherosclerosis 196:659–666. doi:10.1016/j.atherosclerosis.2007.07.022
73. Hoover-Plow J, Huang M (2013) Lipoprotein(a) metabolism: potential sites for therapeutic targets. Metabolism 62:479–491. doi:10.1016/j.metabol.2012.07.024
74. Hori M, Ishihara M, Yuasa Y, Makino H, Yanagi K, Tamanaha T, Kishimoto I, Kujiraoka T, Hattori H, Harada-Shiba M (2014) Removal of plasma mature and furin-cleaved proprotein convertase subtilisin/kexin 9 (PCSK9) by low-density lipoprotein-apheresis in familial hypercholesterolemia: development and application of a new assay for PCSK9. J Clin Endocrinol Metab. doi:10.1210/jc.2014-3066
75. Horton JD, Cohen JC, Hobbs HH (2007) Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci 32:71–77. doi:10.1016/j.tibs.2006.12.008
76. Huijgen R, Boekholdt SM, Arsenault BJ, Bao W, Davaine JM, Tabet F, Petrides F, Rye KA, DeMicco DA, Barter PJ, Kastelein JJ, Lambert G (2012) Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) trial: a nested case-control study. J Am Coll Cardiol 59:1778–1784. doi:10.1016/j.jacc.2011.12.043
77. Ishibashi M, Masson D, Westerterp M, Wang N, Sayers S, Li R, Welch CL, Tall AR (2010) Reduced VLDL clearance in Apoe(-/-)Npc1(-/-) mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels. J Lipid Res 51:2655–2663. doi:10.1194/jlr.M006163
78. Jelassi A, Najah M, Slimani A, Jguirim I, Slimane MN, Varret M (2013) Autosomal dominant hypercholesterolemia: needs for early diagnosis and cascade screening in the tunisian population. Curr Genomics 14:25–32. doi:10.2174/138920213804999200
79. Jin K, Park BS, Kim YW, Vaziri ND (2014) Plasma PCSK9 in nephrotic syndrome and in peritoneal dialysis: a cross-sectional study. Am J Kidney Dis 63:584–589. doi:10.1053/j.ajkd.2013.10.042
80. Kappelle PJ, Lambert G, Dullaart RP (2011) Plasma proprotein convertase subtilisin-kexin type 9 does not change during 24 h insulin infusion in healthy subjects and type 2 diabetic patients. Atherosclerosis 214:432–435. doi:10.1016/j.atherosclerosis.2010.10.028
81. Koren MJ, Giugliano RP, Raal FJ, Sullivan D, Bolognese M, Langslet G, Civeira F, Somaratne R, Nelson P, Liu T, Scott R, Wasserman SM, Sabatine MS (2014) 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 129:234–243. doi:10.1161/CIRCULATIONAHA.113.007012
82. Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J, Kim JB, Scott R, Wasserman SM, Bays H (2014) Anti-PCSK9 monotherapy for hypercholesterolemia: The MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 63:2531–2540. doi:10.1016/j.jacc.2014.03.018
83. Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L, Bolognese M, Wasserman SM (2012) 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 380:1995–2006. doi:10.1016/S0140-6736(12)61771-1
84. Kosenko T, Golder M, Leblond G, Weng W, Lagace TA (2013) 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 288:8279–8288. doi:10.1074/jbc.M112.421370
85. Kourimate S, Le MC, Langhi C, Jarnoux AL, Ouguerram K, Zair Y, Nguyen P, Krempf M, Cariou B, Costet P (2008) Dual mechanisms for the fibrate-mediated repression of proprotein convertase subtilisin/kexin type 9. J Biol Chem 283:9666–9673. doi:10.1074/jbc.M705831200
86. Kuhnast S, van der Hoorn JW, Pieterman EJ, van den Hoek AM, Sasiela WJ, Gusarova V, Peyman A, Schafer HL, Schwahn U, Jukema JW, Princen HM (2014) Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin. J Lipid Res 55:2103–2112. doi:10.1194/jlr.M051326
87. Kwakernaak AJ, Lambert G, Slagman MC, Waanders F, Laverman GD, Petrides F, Dikkeschei BD, Navis G, Dullaart RP (2013) Proprotein convertase subtilisin-kexin type 9 is elevated in proteinuric subjects: relationship with lipoprotein response to antiproteinuric treatment. Atherosclerosis 226:459–465. doi:10.1016/j.atherosclerosis.2012.11.009
88. Kysenius K, Muggalla P, Matlik K, Arumae U, Huttunen HJ (2012) PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling. Cell Mol Life Sci 69:1903–1916. doi:10.1007/s00018-012-0977-6
89. Labonte P, Begley S, Guevin C, Asselin MC, Nassoury N, Mayer G, Prat A, Seidah NG (2009) PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology 50:17–24. doi:10.1002/hep.22911
90. Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH (2009) Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab 94:2537–2543. doi:10.1210/jc.2009-0141
91. Lambert G, Ancellin N, Charlton F, Comas D, Pilot J, Keech A, Patel S, Sullivan DR, Cohn JS, Rye KA, Barter PJ (2008) Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment. Clin Chem 54:1038–1045. doi:10.1373/clinchem.2007.099747
92. Lambert G, Petrides F, Chatelais M, Blom DJ, Choque B, Tabet F, Wong G, Rye KA, Hooper AJ, Burnett JR, Barter PJ, Marais AD (2014) Elevated plasma PCSK9 level is equally detrimental for patients with nonfamilial hypercholesterolemia and heterozygous familial hypercholesterolemia, irrespective of low-density lipoprotein receptor defects. J Am Coll Cardiol 63:2365–2373. doi:10.1016/j.jacc.2014.02.538
93. Langhi C, Le MC, Kourimate S, Caron S, Staels B, Krempf M, Costet P, Cariou B (2008) Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. FEBS Lett 582:949–955. doi:10.1016/j.febslet.2008.02.038
94. Le MC, Berger JM, Lespine A, Pillot B, Prieur X, Letessier E, Hussain MM, Collet X, Cariou B, Costet P (2013) Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1. Arterioscler Thromb Vasc Biol 33:1484–1493. doi:10.1161/ATVBAHA.112.300263
95. Le MC, Kourimate S, Langhi C, Chetiveaux M, Jarry A, Comera C, Collet X, Kuipers F, Krempf M, Cariou B, Costet P (2009) Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. Arterioscler Thromb Vasc Biol 29:684–690. doi:10.1161/ATVBAHA.108.181586
96. Lee CJ, Lee YH, Park SW, Kim KJ, Park S, Youn JC, Lee SH, Kang SM, Jang Y (2013) Association of serum proprotein convertase subtilisin/kexin type 9 with carotid intima media thickness in hypertensive subjects. Metabolism 62:845–850. doi:10.1016/j.metabol.2013.01.005
97. Leren TP (2004) Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet 65:419–422. doi:10.1111/j.0009-9163.2004.0238.x
98. Levy E, Ben Djoudi OA, Spahis S, Sane AT, Garofalo C, Grenier E, Emonnot L, Yara S, Couture P, Beaulieu JF, Menard D, Seidah NG, Elchebly M (2013) PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells. Atherosclerosis 227:297–306. doi:10.1016/j.atherosclerosis.2013.01.023
99. Li H, Dong B, Park SW, Lee HS, Chen W, Liu J (2009) Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J Biol Chem 284:28885–28895. doi:10.1074/jbc.M109.052407
100. Li H, Liu J (2012) The novel function of HINFP as a co-activator in sterol-regulated transcription of PCSK9 in HepG2 cells. Biochem J 443:757–768. doi:10.1042/BJ20111645
101. Li J, Tumanut C, Gavigan JA, Huang WJ, Hampton EN, Tumanut R, Suen KF, Trauger JW, Spraggon G, Lesley SA, Liau G, Yowe D, Harris JL (2007) Secreted PCSK9 promotes LDL receptor degradation independently of proteolytic activity. Biochem J 406:203–207. doi:10.1042/BJ20070664
102. Li S, Guo YL, Xu RX, Zhang Y, Zhu CG, Sun J, Qing P, Wu NQ, Jiang LX, Li JJ (2014) Association of plasma PCSK9 levels with white blood cell count and its subsets in patients with stable coronary artery disease. Atherosclerosis 234:441–445. doi:10.1016/j.atherosclerosis.2014.04.001
103. Lindholm MW, Elmen J, Fisker N, Hansen HF, Persson R, Moller MR, Rosenbohm C, Orum H, Straarup EM, Koch T (2012) PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol Ther 20:376–381. doi:10.1038/mt.2011.260
104. Lipari MT, Li W, Moran P, Kong-Beltran M, Sai T, Lai J, Lin SJ, Kolumam G, Zavala-Solorio J, Izrael-Tomasevic A, Arnott D, Wang J, Peterson AS, Kirchhofer D (2012) Furin-cleaved proprotein convertase subtilisin/kexin type 9 (PCSK9) is active and modulates low density lipoprotein receptor and serum cholesterol levels. J Biol Chem 287:43482–43491. doi:10.1074/jbc.M112.380618
105. Liu M, Wu G, Baysarowich J, Kavana M, Addona GH, Bierilo KK, Mudgett JS, Pavlovic G, Sitlani A, Renger JJ, Hubbard BK, Fisher TS, Zerbinatti CV (2010) PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain. J Lipid Res 51:2611–2618. doi:10.1194/jlr.M006635
106. Mabuchi H, Nohara A, Noguchi T, Kobayashi J, Kawashiri MA, Inoue T, Mori M, Tada H, Nakanishi C, Yagi K, Yamagishi M, Ueda K, Takegoshi T, Miyamoto S, Inazu A, Koizumi J (2014) Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation. Atherosclerosis 236:54–61. doi:10.1016/j.atherosclerosis.2014.06.005
107. Maxwell KN, Breslow JL (2004) Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA 101:7100–7105. doi:10.1073/pnas.0402133101
108. Maxwell KN, Fisher EA, Breslow JL (2005) Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA 102:2069–2074. doi:10.1073/pnas.0409736102
109. Mayer G, Poirier S, Seidah NG (2008) Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels. J Biol Chem 283:31791–31801. doi:10.1074/jbc.M805971200
110. Mayne J, Dewpura T, Raymond A, Cousins M, Chaplin A, Lahey KA, Lahaye SA, Mbikay M, Ooi TC, Chretien M (2008) Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis 7:22. doi:10.1186/1476-511X-7-22
111. Mbikay M, Sirois F, Gyamera-Acheampong C, Wang GS, Rippstein P, Chen A, Mayne J, Scott FW, Chretien M (2014) Variable effects of gender and Western diet on lipid and glucose homeostasis in aged PCSK9-deficient C57BL/6 mice. J Diabetes. doi:10.1111/1753-0407.12139
112. Mbikay M, Sirois F, Mayne J, Wang GS, Chen A, Dewpura T, Prat A, Seidah NG, Chretien M, Scott FW (2010) PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett 584:701–706. doi:10.1016/j.febslet.2009.12.018
113. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA (2012) 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 59:2344–2353. doi:10.1016/j.jacc.2012.03.007
114. McNutt MC, Kwon HJ, Chen C, Chen JR, Horton JD, Lagace TA (2009) Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J Biol Chem 284:10561–10570. doi:10.1074/jbc.M808802200
115. McNutt MC, Lagace TA, Horton JD (2007) Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells. J Biol Chem 282:20799–20803. doi:10.1074/jbc.C700095200
116. Melone M, Wilsie L, Palyha O, Strack A, Rashid S (2012) 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 59:1697–1705. doi:10.1016/j.jacc.2011.11.064
117. Miranda MX, van Tits LJ, Lohmann C, Arsiwala T, Winnik S, Tailleux A, Stein S, Gomes AP, Suri V, Ellis JL, Lutz TA, Hottiger MO, Sinclair DA, Auwerx J, Schoonjans K, Staels B, Luscher TF, Matter CM (2014) The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression. Eur Heart J. doi:10.1093/eurheartj/ehu095
118. Mitchell T, Chao G, Sitkoff D, Lo F, Monshizadegan H, Meyers D, Low S, Russo K, DiBella R, Denhez F, Gao M, Myers J, Duke G, Witmer M, Miao B, Ho SP, Khan J, Parker RA (2014) Pharmacologic profile of the adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. J Pharmacol Exp Ther 350:412–424. doi:10.1124/jpet.114.214221
119. Ni YG, Di MS, Condra JH, Peterson LB, Wang W, Wang F, Pandit S, Hammond HA, Rosa R, Cummings RT, Wood DD, Liu X, Bottomley MJ, Shen X, Cubbon RM, Wang SP, Johns DG, Volpari C, Hamuro L, Chin J, Huang L, Zhao JZ, Vitelli S, Haytko P, Wisniewski D, Mitnaul LJ, Sparrow CP, Hubbard B, Carfi A, Sitlani A (2011) A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo. J Lipid Res 52:78–86. doi:10.1194/jlr.M011445
120. Noguchi T, Kobayashi J, Yagi K, Nohara A, Yamaaki N, Sugihara M, Ito N, Oka R, Kawashiri MA, Tada H, Takata M, Inazu A, Yamagishi M, Mabuchi H (2011) 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 217:165–170. doi:10.1016/j.atherosclerosis.2011.02.012
121. Norata GD, Garlaschelli K, Grigore L, Raselli S, Tramontana S, Meneghetti F, Artali R, Noto D, Cefalu AB, Buccianti G, Averna M, Catapano AL (2010) Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles. Atherosclerosis 208:177–182. doi:10.1016/j.atherosclerosis.2009.06.023
122. Norata GD, Tibolla G, Catapano AL (2014) Targeting PCSK9 for hypercholesterolemia. Annu Rev Pharmacol Toxicol 54:273–293. doi:10.1146/annurev-pharmtox-011613-140025
123. Nozue T, Hattori H, Ishihara M, Iwasaki T, Hirano T, Kawashiri MA, Yamagishi M, Michishita I (2013) Comparison of effects of pitavastatin versus pravastatin on serum proprotein convertase subtilisin/kexin type 9 levels in statin-naive patients with coronary artery disease. Am J Cardiol 111:1415–1419. doi:10.1016/j.amjcard.2013.01.289
124. Park SW, Moon YA, Horton JD (2004) Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 279:50630–50638. doi:10.1074/jbc.M410077200
125. Persson L, Cao G, Stahle L, Sjoberg BG, Troutt JS, Konrad RJ, Galman C, Wallen H, Eriksson M, Hafstrom I, Lind S, Dahlin M, Amark P, Angelin B, Rudling M (2010) Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans. Arterioscler Thromb Vasc Biol 30:2666–2672. doi:10.1161/ATVBAHA.110.214130
126. Persson L, Henriksson P, Westerlund E, Hovatta O, Angelin B, Rudling M (2012) Endogenous estrogens lower plasma PCSK9 and LDL cholesterol but not Lp(a) or bile acid synthesis in women. Arterioscler Thromb Vasc Biol 32:810–814. doi:10.1161/ATVBAHA.111.242461
127. Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J, Nassoury N, Mayer H, Nimpf J, Prat A, Seidah NG (2008) The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J Biol Chem 283:2363–2372. doi:10.1074/jbc.M708098200
128. Poirier S, Prat A, Marcinkiewicz E, Paquin J, Chitramuthu BP, Baranowski D, Cadieux B, Bennett HP, Seidah NG (2006) Implication of the proprotein convertase NARC-1/PCSK9 in the development of the nervous system. J Neurochem 98:838–850. doi:10.1111/j.1471-4159.2006.03928.x
129. Postmus I, Trompet S, de Craen AJ, Buckley BM, Ford I, Stott DJ, Sattar N, Slagboom PE, Westendorp RG, Jukema JW (2013) 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 54:561–566. doi:10.1194/jlr.P033969
130. Qian YW, Schmidt RJ, Zhang Y, Chu S, Lin A, Wang H, Wang X, Beyer TP, Bensch WR, Li W, Ehsani ME, Lu D, Konrad RJ, Eacho PI, Moller DE, Karathanasis SK, Cao G (2007) Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J Lipid Res 48:1488–1498. doi:10.1194/jlr.M700071-JLR200
131. Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, Stein EA (2012) 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 126:2408–2417. doi:10.1161/CIRCULATIONAHA.112.144055
132. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, Blom D, Eriksson M, Dent R, Wasserman SM, Huang F, Xue A, Albizem M, Scott R, Stein EA (2014) Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 63:1278–1288. doi:10.1016/j.jacc.2014.01.006
133. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, Wasserman SM, Stein EA (2014) Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. doi:10.1016/S0140-6736(14)61374-X
134. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, Langslet G, Scott R, Olsson AG, Sullivan D, Hovingh GK, Cariou B, Gouni-Berthold I, Somaratne R, Bridges I, Scott R, Wasserman SM, Gaudet D (2014) PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. doi:10.1016/S0140-6736(14)61399-4
135. Rashid S, Tavori H, Brown PE, Linton MF, He J, Giunzioni I, Fazio S (2014) 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 130:431–441. doi:10.1161/CIRCULATIONAHA.113.006720
136. Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D, Somaratne R, Legg JC, Nelson P, Scott R, Wasserman SM, Weiss R (2014) Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA 311:1870–1882. doi:10.1001/jama.2014.4030
137. Roche-Molina M, Sanz-Rosa D, Cruz FM, Garcia-Prieto J, Lopez S, Abia R, Muriana FJ, Fuster V, Ibanez B, Bernal JA (2014) Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9. Arterioscler Thromb Vasc Biol 35:50–59. doi:10.1161/ATVBAHA.114.303617
138. Romano M, Di Taranto MD, D’Agostino MN, Marotta G, Gentile M, Abate G, Mirabelli P, Di NR, Del VL, Rubba P, Fortunato G (2010) Identification and functional characterization of LDLR mutations in familial hypercholesterolemia patients from Southern Italy. Atherosclerosis 210:493–496. doi:10.1016/j.atherosclerosis.2009.11.051
139. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA (2012) Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 367:1891–1900. doi:10.1056/NEJMoa1201832
140. Roth EM, Taskinen MR, Ginsberg HN, Kastelein JJ, Colhoun HM, Robinson JG, Merlet L, Pordy R, Baccara-Dinet MT (2014) Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: Results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol 176:55–61. doi:10.1016/j.ijcard.2014.06.049
141. Roubtsova A, Munkonda MN, Awan Z, Marcinkiewicz J, Chamberland A, Lazure C, Cianflone K, Seidah NG, Prat A (2011) Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler Thromb Vasc Biol 31:785–791. doi:10.1161/ATVBAHA.110.220988
142. Saavedra YG, Day R, Seidah NG (2012) 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 287:43492–43501. doi:10.1074/jbc.M112.394023
143. Saavedra YG, Dufour R, Davignon J, Baass A (2014) PCSK9 R46L, lower LDL, and cardiovascular disease risk in familial hypercholesterolemia: A cross-sectional cohort study. Arterioscler Thromb Vasc Biol. doi:10.1161/ATVBAHA.114.304406
144. Sasaki M, Terao Y, Ayaori M, Uto-Kondo H, Iizuka M, Yogo M, Hagisawa K, Takiguchi S, Yakushiji E, Nakaya K, Ogura M, Komatsu T, Ikewaki K (2014) Hepatic overexpression of idol increases circulating protein convertase subtilisin/kexin type 9 in mice and hamsters via dual mechanisms: sterol regulatory element-binding protein 2 and low-density lipoprotein receptor-dependent pathways. Arterioscler Thromb Vasc Biol 34:1171–1178. doi:10.1161/ATVBAHA.113.302670
145. Schiele F, Park J, Redemann N, Luippold G, Nar H (2014) An antibody against the C-terminal domain of PCSK9 lowers LDL cholesterol levels in vivo. J Mol Biol 426:843–852. doi:10.1016/j.jmb.2013.11.011
146. Schroeder CI, Swedberg JE, Withka JM, Rosengren KJ, Akcan M, Clayton DJ, Daly NL, Cheneval O, Borzilleri KA, Griffor M, Stock I, Colless B, Walsh P, Sunderland P, Reyes A, Dullea R, Ammirati M, Liu S, McClure KF, Tu M, Bhattacharya SK, Liras S, Price DA, Craik DJ (2014) Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro. Chem Biol 21:284–294. doi:10.1016/j.chembiol.2013.11.014
147. Scotti E, Calamai M, Goulbourne CN, Zhang L, Hong C, Lin RR, Choi J, Pilch PF, Fong LG, Zou P, Ting AY, Pavone FS, Young SG, Tontonoz P (2013) IDOL stimulates clathrin-independent endocytosis and multivesicular body-mediated lysosomal degradation of the low-density lipoprotein receptor. Mol Cell Biol 33:1503–1514. doi:10.1128/MCB.01716-12
148. Scotti E, Hong C, Yoshinaga Y, Tu Y, Hu Y, Zelcer N, Boyadjian R, de Jong PJ, Young SG, Fong LG, Tontonoz P (2011) Targeted disruption of the idol gene alters cellular regulation of the low-density lipoprotein receptor by sterols and liver x receptor agonists. Mol Cell Biol 31:1885–1893. doi:10.1128/MCB.01469-10
149. Seidah NG (2011) The proprotein convertases, 20 years later. Methods Mol Biol 768:23–57. doi:10.1007/978-1-61779-204-5_3
150. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M (2003) The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA 100:928–933. doi:10.1073/pnas.0335507100
151. Seidah NG, Poirier S, Denis M, Parker R, Miao B, Mapelli C, Prat A, Wassef H, Davignon J, Hajjar KA, Mayer G (2012) Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. PLoS One 7:e41865. doi:10.1371/journal.pone.0041865
152. Shan L, Pang L, Zhang R, Murgolo NJ, Lan H, Hedrick JA (2008) PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide. Biochem Biophys Res Commun 375:69–73. doi:10.1016/j.bbrc.2008.07.106
153. Sharotri V, Collier DM, Olson DR, Zhou R, Snyder PM (2012) Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). J Biol Chem 287:19266–19274. doi:10.1074/jbc.M112.363382
154. Shen L, Peng HC, Nees SN, Zhao SP, Xu DY (2013) Proprotein convertase subtilisin/kexin type 9 potentially influences cholesterol uptake in macrophages and reverse cholesterol transport. FEBS Lett 587:1271–1274. doi:10.1016/j.febslet.2013.02.027
155. Sodhi N, Krasuski RA (2013) Therapy and clinical trials. Curr Opin Lipidol 24:281–282. doi:10.1097/MOL.0b013e3283616351
156. Sorrentino V, Fouchier SW, Motazacker MM, Nelson JK, Defesche JC, Dallinga-Thie GM, Kastelein JJ, Kees HG, Zelcer N (2013) Identification of a loss-of-function inducible degrader of the low-density lipoprotein receptor variant in individuals with low circulating low-density lipoprotein. Eur Heart J 34:1292–1297. doi:10.1093/eurheartj/ehs472
157. Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, Wu R, Pordy R (2012) Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 380:29–36. doi:10.1016/S0140-6736(12)60771-5
158. Stein EA, Giugliano RP, Koren MJ, Raal FJ, Roth EM, Weiss R, Sullivan D, Wasserman SM, Somaratne R, Kim JB, Yang J, Liu T, Albizem M, Scott R, Sabatine MS (2014) Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur Heart J. doi:10.1093/eurheartj/ehu085
159. Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ (2013) Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 128:2113–2120. doi:10.1161/CIRCULATIONAHA.113.004678
160. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, Lisbon E, Gutierrez M, Webb C, Wu R, Du Y, Kranz T, Gasparino E, Swergold GD (2012) Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 366:1108–1118. doi:10.1056/NEJMoa1105803
161. Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, Bruckert E, Cho L, Dent R, Knusel B, Xue A, Scott R, Wasserman SM, Rocco M (2014) 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 63:2541–2548. doi:10.1016/j.jacc.2014.03.019
162. Strom TB, Holla OL, Tveten K, Cameron J, Berge KE, Leren TP (2010) Disrupted recycling of the low density lipoprotein receptor by PCSK9 is not mediated by residues of the cytoplasmic domain. Mol Genet Metab 101:76–80. doi:10.1016/j.ymgme.2010.05.003
163. Strom TB, Tveten K, Leren TP (2014) PCSK9 acts as a chaperone for the LDL receptor in the endoplasmic reticulum. Biochem J 457:99–105. doi:10.1042/BJ20130930
164. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V, Wasserman SM, Stein EA (2012) Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 308:2497–2506. doi:10.1001/jama.2012.25790
165. Tang Z, Jiang L, Peng J, Ren Z, Wei D, Wu C, Pan L, Jiang Z, Liu L (2012) PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-kappaB activation in THP-1-derived macrophages. Int J Mol Med 30:931–938. doi:10.3892/ijmm.2012.1072
166. Tao R, Xiong X, DePinho RA, Deng CX, Dong XC (2013) FoxO3 transcription factor and Sirt6 deacetylase regulate low density lipoprotein (LDL)-cholesterol homeostasis via control of the proprotein convertase subtilisin/kexin type 9 (Pcsk9) gene expression. J Biol Chem 288:29252–29259. doi:10.1074/jbc.M113.481473
167. Tavori H, Fan D, Blakemore JL, Yancey PG, Ding L, Linton MF, Fazio S (2013) Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation. Circulation 127:2403–2413. doi:10.1161/CIRCULATIONAHA.113.001592
168. Tavori H, Giunzioni I, Linton MF, Fazio S (2013) Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis. Circ Res 113:1290–1295. doi:10.1161/CIRCRESAHA.113.302655
169. Troutt JS, Alborn WE, Cao G, Konrad RJ (2010) Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels. J Lipid Res 51:345–351. doi:10.1194/jlr.M000620
170. Urban D, Poss J, Bohm M, Laufs U (2013) Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J Am Coll Cardiol 62:1401–1408. doi:10.1016/j.jacc.2013.07.056
171. Walley KR, Thain KR, Russell JA, Reilly MP, Meyer NJ, Ferguson JF, Christie JD, Nakada TA, Fjell CD, Thair SA, Cirstea MS, Boyd JH (2014) PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med 6:25843. doi:10.1126/scitranslmed.3008782
172. Wang Y, Huang Y, Hobbs HH, Cohen JC (2012) Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR. J Lipid Res 53:1932–1943. doi:10.1194/jlr.M028563
173. Werner C, Hoffmann MM, Winkler K, Bohm M, Laufs U (2014) Risk prediction with proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with stable coronary disease on statin treatment. Vascul Pharmacol 62:94–102. doi:10.1016/j.vph.2014.03.004
174. Wu CY, Tang ZH, Jiang L, Li XF, Jiang ZS, Liu LS (2012) PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3 pathway. Mol Cell Biochem 359:347–358. doi:10.1007/s11010-011-1028-6
175. Wu M, Dong B, Cao A, Li H, Liu J (2012) Delineation of molecular pathways that regulate hepatic PCSK9 and LDL receptor expression during fasting in normolipidemic hamsters. Atherosclerosis 224:401–410. doi:10.1016/j.atherosclerosis.2012.08.012
176. Wu Q, Tang ZH, Peng J, Liao L, Pan LH, Wu CY, Jiang ZS, Wang GX, Liu LS (2014) The dual behavior of PCSK9 in the regulation of apoptosis is crucial in Alzheimer’s disease progression (Review). Biomed Rep 2:167–171. doi:10.3892/br.2013.213
177. Xiao HB, Sun ZL, Zhang HB, Zhang DS (2012) Berberine inhibits dyslipidemia in C57BL/6 mice with lipopolysaccharide induced inflammation. Pharmacol Rep 64:889–895
178. Xu W, Liu L, Hornby D (2012) c-IAP1 binds and processes PCSK9 protein: linking the c-IAP1 in a TNF-alpha pathway to PCSK9-mediated LDLR degradation pathway. Molecules 17:12086–12101. doi:10.3390/molecules171012086
179. Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD, Cohen JC, Hobbs HH (2007) 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 282:18602–18612. doi:10.1074/jbc.M702027200
180. Zhang Y, Eigenbrot C, Zhou L, Shia S, Li W, Quan C, Tom J, Moran P, Di LP, Skelton NJ, Kong-Beltran M, Peterson A, Kirchhofer D (2014) Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor. J Biol Chem 289:942–955. doi:10.1074/jbc.M113.514067
181. Zhang Y, Zhu CG, Xu RX, Li S, Guo YL, Sun J, Li JJ (2014) Relation of circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease. J Clin Lipidol 8:494–500. doi:10.1016/j.jacl.2014.07.001