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Proprotein Convertase Subtilisin/Kexin-Type 9 and Lipid Metabolism

Chapter
First Online:
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1276)

Abstract

Plasma levels of cholesterol, especially low-density lipoprotein cholesterol (LDL-C), are positively correlated with the risk of cardiovascular disease. Buildup of LDL in the intima promotes the formation of foam cells and consequently initiates atherosclerosis, one of the main underlying causes of cardiovascular disease. Hepatic LDL receptor (LDLR) is mainly responsible for the clearance of plasma LDL. Mutations in LDLR cause familiar hypercholesterolemia and increase the risk of premature coronary heart disease. Proprotein convertase subtilisin/kexin-type 9 (PCSK9) promotes LDLR degradation and thereby plays a critical role in the regulation of plasma cholesterol metabolism. PCSK9 can bind to LDLR and reroute the receptor to lysosomes for degradation, increasing both circulating LDL-C levels and the risk of cardiovascular disease. PCSK9 is mainly regulated by sterol response element binding protein 2 (SREBP2) at the transcriptional level. Furthermore, many proteins have been identified as interacting with PCSK9, regulating plasma cholesterol levels. Pharmacotherapeutic inhibition of PCSK9 dramatically reduces plasma levels of LDL cholesterol and significantly reduces cardiovascular events. In this article, we summarize the latest advances in PCSK9, mainly focusing on the structure, function, and regulation of the protein, the underlying molecular mechanisms, and its pharmacotherapeutic applications.

Keywords

Hypercholesterolemia Low-density lipoprotein receptor Statin Atherosclerosis Proprotein convertase subtilisin/kexin-type 9 

Abbreviations

ADH

autosomal dominant hypercholesterolemia

Apo

apolipoprotein

ARH

autosomal recessive hypercholesterolemia

BACE1

β-site amyloid precursor protein-cleaving enzyme 1

bHLH

basic helix-loop-helix

CAP1

cyclase-associated protein 1

CAT

catalytic domain

COPII

the coat protein complex II

CSF

cerebrospinal fluid

CM

C-terminal module

CTD

C-terminal domain

CVD

cardiovascular disease

EGF-A

the epidermal growth factor precursor homology domain A

Epac2

exchange protein activated by cAMP-2

ER

endoplasmic reticulum

ERGIC

ER-Golgi intermediate compartment

FH

familial hypercholesterolemia

GPC3

glypican-3

HDL

high-density lipoprotein

HINFP

histone nuclear factor P

HMGCR

3-hydroxyl-3-methylglutaryl-CoA reductase

HNF1

hepatocyte nuclear factor 1

HSPG

heparan sulfate proteoglycan

INSIG

insulin-induced gene protein

LDL-C

low-density lipoprotein cholesterol

LDLR

LDL receptor

Lp(a)

lipoprotein (a)

miRNA

microRNA

PC

proprotein convertase

PCSK9

proprotein convertase subtilisin kexin-like 9

PLTP

phospholipid transfer protein

Rap1

ras-related protein-1

RISC

RNA-induced silencing complex

S1P

site-1 proteinase

S2P

site-2 proteinase

SCAP

SREBP cleavage activating protein

siRNA

small interfering RNA

SREBP-2

sterol regulatory element binding protein 2

Surf4

Surfeit 4

TLP

Toll-like receptor

UTR

untranslated region

VLDLR

very low-density lipoprotein receptor

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Notes

Acknowledgments

This chapter was partially overlapped with the paper published by our group in The Journal of Biomedical Research (Gu and Zhang 2015; 29: 356–361). Zhang laboratory is supported by grants from the Natural Sciences and Engineering Research Council of Canada (RGPIN-2016-06479), the Canadian Institutes of Health Research (PS 155994), a Grant-in-Aid from the Heart and Stroke Foundation of Canada, and Pfizer Canada (PI ASPIRECCRG W1218248).

References

  1. 1.
    Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874PubMedGoogle Scholar
  2. 2.
    Goldstein JL, Brown MS (2009) The LDL receptor. Arterioscler Thromb Vasc Biol 29:431–438PubMedPubMedCentralGoogle Scholar
  3. 3.
    Tiwari RL, Singh V, Barthwal MK (2008) Macrophages: an elusive yet emerging therapeutic target of atherosclerosis. Med Res Rev 28:483–544PubMedGoogle Scholar
  4. 4.
    Platt N, Gordon S (2001) Is the class A macrophage scavenger receptor (SR-A) multifunctional? – The mouse’s tale. J Clin Invest 108:649–654PubMedPubMedCentralGoogle Scholar
  5. 5.
    Quiroga AD, Lehner R (2012) Liver triacylglycerol lipases. Biochim Biophys Acta 1821:762–769PubMedGoogle Scholar
  6. 6.
    Brown MS, Goldstein JL (2006) Biomedicine. Lowering LDL – not only how low, but how long? Science 311:1721–1723PubMedGoogle Scholar
  7. 7.
    Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34:154–156PubMedGoogle Scholar
  8. 8.
    Leren TP (2004) Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet 65:419–422PubMedGoogle Scholar
  9. 9.
    Abifadel M, Rabes JP, Devillers M, Munnich A, Erlich D, Junien C, Varret M, Boileau C (2009) Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat 30:520–529PubMedGoogle Scholar
  10. 10.
    Gu HM, Zhang DW (2015) Hypercholesterolemia, low density lipoprotein receptor and proprotein convertase subtilisin/kexin-type 9. J Biomed Res 29:356–361PubMedPubMedCentralGoogle Scholar
  11. 11.
    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 354:1264–1272PubMedGoogle Scholar
  12. 12.
    Seidah NG, Khatib AM, Prat A (2006) The proprotein convertases and their implication in sterol and/or lipid metabolism. Biol Chem 387:871–877PubMedGoogle Scholar
  13. 13.
    Abifadel M, Rabes JP, Jambart S, Halaby G, Gannage-Yared MH, Sarkis A, Beaino G, Varret M, Salem N, Corbani S, Aydenian H, Junien C, Munnich A, Boileau C (2009) The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene. Hum Mutat 30:E682–E691PubMedGoogle Scholar
  14. 14.
    Seidah NG, Mayer G, Zaid A, Rousselet E, Nassoury N, Poirier S, Essalmani R, Prat A (2008) The activation and physiological functions of the proprotein convertases. Int J Biochem Cell Biol 40:1111–1125PubMedGoogle Scholar
  15. 15.
    Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, Subashi TA, Varghese AH, Ammirati MJ, Culp JS, Hoth LR, Mansour MN, McGrath KM, Seddon AP, Shenolikar S, Stutzman-Engwall KJ, Warren LC, Xia D, Qiu X (2007) Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Mol Biol 14:413–419PubMedGoogle Scholar
  16. 16.
    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 286:43054–43061PubMedPubMedCentralGoogle Scholar
  17. 17.
    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 287:43492–43501PubMedGoogle Scholar
  18. 18.
    Hampton EN, Knuth MW, Li J, Harris JL, Lesley SA, Spraggon G (2007) The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain. Proc Natl Acad Sci U S A 104:14604–14609PubMedPubMedCentralGoogle Scholar
  19. 19.
    Piper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, Thibault ST, Shan B, Walker NP (2007) The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure 15:545–552PubMedGoogle Scholar
  20. 20.
    Kwon HJ, Lagace TA, McNutt MC, Horton JD, Deisenhofer J (2008) Molecular basis for LDL receptor recognition by PCSK9. Proc Natl Acad Sci U S A 105:1820–1825PubMedPubMedCentralGoogle Scholar
  21. 21.
    Henrich S, Lindberg I, Bode W, Than ME (2005) Proprotein convertase models based on the crystal structures of furin and kexin: explanation of their specificity. Journal of molecular biology 345:211–227PubMedGoogle Scholar
  22. 22.
    Holyoak T, Wilson MA, Fenn TD, Kettner CA, Petsko GA, Fuller RS, Ringe D (2003) 2.4 A resolution crystal structure of the prototypical hormone-processing protease Kex2 in complex with an Ala-Lys-Arg boronic acid inhibitor. Biochemistry 42:6709–6718PubMedGoogle Scholar
  23. 23.
    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA (2001) The hormone resistin links obesity to diabetes. Nature 409:307–312PubMedGoogle Scholar
  24. 24.
    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 U S A 100:928–933PubMedPubMedCentralGoogle Scholar
  25. 25.
    Zaid A, Roubtsova A, Essalmani R, Marcinkiewicz J, Chamberland A, Hamelin J, Tremblay M, Jacques H, Jin W, Davignon J, Seidah NG, Prat A (2008) Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology 48:646–654PubMedGoogle Scholar
  26. 26.
    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 279:48865–48875PubMedGoogle Scholar
  27. 27.
    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 203:161–165PubMedGoogle Scholar
  28. 28.
    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 287:33745–33755PubMedPubMedCentralGoogle Scholar
  29. 29.
    Chorba JS, Galvan AM, Shokat KM (2018) Stepwise processing analyses of the single-turnover PCSK9 protease reveal its substrate sequence specificity and link clinical genotype to lipid phenotype. J Biol Chem 293:1875–1886PubMedGoogle Scholar
  30. 30.
    Deng SJ, Shen Y, Gu HM, Guo S, Wu SR, Zhang DW (2020) The role of the C-terminal domain of PCSK9 and SEC24 isoforms in PCSK9 secretion. Biochim Biophys Acta Mol Cell Biol Lipids 1865:158660Google Scholar
  31. 31.
    Wieland FT, Gleason ML, Serafini TA, Rothman JE (1987) The rate of bulk flow from the endoplasmic reticulum to the cell surface. Cell 50:289–300PubMedGoogle Scholar
  32. 32.
    Martinez-Menarguez JA, Geuze HJ, Slot JW, Klumperman J (1999) Vesicular tubular clusters between the ER and Golgi mediate concentration of soluble secretory proteins by exclusion from COPI-coated vesicles. Cell 98:81–90PubMedGoogle Scholar
  33. 33.
    Dancourt J, Barlowe C (2010) Protein sorting receptors in the early secretory pathway. Annu Rev Biochem 79:777–802PubMedGoogle Scholar
  34. 34.
    Szul T, Sztul E (2011) COPII and COPI traffic at the ER-Golgi interface. Physiology (Bethesda) 26:348–364Google Scholar
  35. 35.
    Mizuno M, Singer SJ (1993) A soluble secretory protein is first concentrated in the endoplasmic reticulum before transfer to the Golgi apparatus. Proc Natl Acad Sci U S A 90:5732–5736PubMedPubMedCentralGoogle Scholar
  36. 36.
    Zhang B, Cunningham MA, Nichols WC, Bernat JA, Seligsohn U, Pipe SW, McVey JH, Schulte-Overberg U, de Bosch NB, Ruiz-Saez A, White GC, Tuddenham EG, Kaufman RJ, Ginsburg D (2003) Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex. Nat Genet 34:220–225PubMedGoogle Scholar
  37. 37.
    Nyfeler B, Reiterer V, Wendeler MW, Stefan E, Zhang B, Michnick SW, Hauri HP (2008) Identification of ERGIC-53 as an intracellular transport receptor of alpha1-antitrypsin. J Cell Biol 180:705–712PubMedPubMedCentralGoogle Scholar
  38. 38.
    Hara-Kuge S, Ohkura T, Ideo H, Shimada O, Atsumi S, Yamashita K (2002) Involvement of VIP36 in intracellular transport and secretion of glycoproteins in polarized Madin-Darby canine kidney (MDCK) cells. J Biol Chem 277:16332–16339PubMedGoogle Scholar
  39. 39.
    Strating JR, Hafmans TG, Martens GJ (2009) Functional diversity among p24 subfamily members. Biol Cell 101:207–219PubMedGoogle Scholar
  40. 40.
    Neve EP, Svensson K, Fuxe J, Pettersson RF (2003) VIPL, a VIP36-like membrane protein with a putative function in the export of glycoproteins from the endoplasmic reticulum. Exp Cell Res 288:70–83PubMedGoogle Scholar
  41. 41.
    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:e00444PubMedPubMedCentralGoogle Scholar
  42. 42.
    Emmer BT, Hesketh GG, Kotnik E, Tang VT, Lascuna PJ, Xiang J, Gingras AC, Chen XW, Ginsburg D (2018) The cargo receptor SURF4 promotes the efficient cellular secretion of PCSK9. Elife 7:e38839PubMedPubMedCentralGoogle Scholar
  43. 43.
    Reeves JE, Fried M (1995) The surf-4 gene encodes a novel 30 kDa integral membrane protein. Mol Membr Biol 12:201–208PubMedGoogle Scholar
  44. 44.
    Shen Y, Wang B, Deng S, Zhai L, Gu HM, Alabi A, Xia X, Zhao Y, Chang X, Qin S, Zhang DW (2020) Surf4 regulates expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) but is not required for PCSK9 secretion in cultured human hepatocytes. Biochim Biophys Acta Mol Cell Biol Lipids 1865:158555PubMedGoogle Scholar
  45. 45.
    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 19:310–318PubMedGoogle Scholar
  46. 46.
    Butkinaree C, Canuel M, Essalmani R, Poirier S, Benjannet S, Asselin MC, Roubtsova A, Hamelin J, Marcinkiewicz J, Chamberland A, Guillemot J, Mayer G, Sisodia SS, Jacob Y, Prat A, Seidah NG (2015) Amyloid precursor-like protein 2 and sortilin do not regulate the PCSK9 convertase-mediated low density lipoprotein receptor degradation but interact with each other. J Biol Chem 290:18609–18620PubMedPubMedCentralGoogle Scholar
  47. 47.
    Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, Krempf M, Reznik Y, Girardet JP, Fredenrich A, Junien C, Varret M, Boileau C, Benlian P, Rabes JP (2005) Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat 26:497PubMedGoogle Scholar
  48. 48.
    Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, Skolnick MH, Hopkins PN, Hunt SC, Shattuck DM (2004) A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet 114:349–353PubMedGoogle Scholar
  49. 49.
    Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37:161–165PubMedGoogle Scholar
  50. 50.
    Folsom AR, Peacock JM, Boerwinkle E (2009) Variation in PCSK9, low LDL cholesterol, and risk of peripheral arterial disease. Atherosclerosis 202:211–215PubMedGoogle Scholar
  51. 51.
    Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, Hobbs HH (2006) A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet 78:410–422PubMedPubMedCentralGoogle Scholar
  52. 52.
    Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR (2007) The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 193:445–448PubMedGoogle Scholar
  53. 53.
    Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH (2006) Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 79:514–523PubMedPubMedCentralGoogle Scholar
  54. 54.
    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 U S A 101:7100–7105PubMedPubMedCentralGoogle Scholar
  55. 55.
    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 279:50630–50638PubMedGoogle Scholar
  56. 56.
    Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, Hammer RE, Moon YA, Horton JD (2005) Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci U S A 102:5374–5379PubMedPubMedCentralGoogle Scholar
  57. 57.
    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 Fougerolles A, 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 U S A 105:11915–11920PubMedPubMedCentralGoogle Scholar
  58. 58.
    Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, Prather HB, Anderson NN, Ho YK, Hammer RE, Horton JD (2006) Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest 116:2995–3005PubMedPubMedCentralGoogle Scholar
  59. 59.
    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 284:10561–10570PubMedPubMedCentralGoogle Scholar
  60. 60.
    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 282:18602–18612PubMedGoogle Scholar
  61. 61.
    Zhang DW, Garuti R, Tang WJ, Cohen JC, Hobbs HH (2008) Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor. Proc Natl Acad Sci U S A 105:13045–13050PubMedPubMedCentralGoogle Scholar
  62. 62.
    Cameron J, Holla OL, Ranheim T, Kulseth MA, Berge KE, Leren TP (2006) Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Hum Mol Genet 15:1551–1558PubMedGoogle Scholar
  63. 63.
    Lalanne F, Lambert G, Amar MJ, Chetiveaux M, Zair Y, Jarnoux AL, Ouguerram K, Friburg J, Seidah NG, Brewer HB Jr, Krempf M, Costet P (2005) Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells. J Lipid Res 46:1312–1319PubMedGoogle Scholar
  64. 64.
    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 48:1488–1498PubMedGoogle Scholar
  65. 65.
    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 53:1932–1943PubMedPubMedCentralGoogle Scholar
  66. 66.
    Fasano T, Sun XM, Patel DD, Soutar AK (2009) Degradation of LDLR protein mediated by ‘gain of function’ PCSK9 mutants in normal and ARH cells. Atherosclerosis 203:166–171PubMedGoogle Scholar
  67. 67.
    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 U S A 102:2069–2074PubMedPubMedCentralGoogle Scholar
  68. 68.
    Sanchez-Hernandez RM, Di Taranto MD, Benito-Vicente A, Uribe KB, Lamiquiz-Moneo I, Larrea-Sebal A, Jebari S, Galicia-Garcia U, Novoa FJ, Boronat M, Wagner AM, Civeira F, Martin C, Fortunato G (2019) The Arg499His gain-of-function mutation in the C-terminal domain of PCSK9. Atherosclerosis 289:162–172PubMedGoogle Scholar
  69. 69.
    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 196:659–666PubMedGoogle Scholar
  70. 70.
    Poirier S, Mayer G, Poupon V, McPherson PS, Desjardins R, Ly K, Asselin MC, Day R, Duclos FJ, Witmer M, Parker R, Prat A, Seidah NG (2009) Dissection of the endogenous cellular pathways of PCSK9-induced LDLR degradation: Evidence for an intracellular route. J Biol Chem 284:28856–28864PubMedPubMedCentralGoogle Scholar
  71. 71.
    Grefhorst A, McNutt MC, Lagace TA, Horton JD (2008) Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J Lipid Res 49:1303–1311PubMedPubMedCentralGoogle Scholar
  72. 72.
    Luo Y, Warren L, Xia D, Jensen H, Sand T, Petras S, Qin W, Miller KS, Hawkins J (2009) Function and distribution of circulating human PCSK9 expressed extrahepatically in transgenic mice. J Lipid Res 50:1581–1588PubMedPubMedCentralGoogle Scholar
  73. 73.
    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 127:2403–2413PubMedPubMedCentralGoogle Scholar
  74. 74.
    Cariou B, Benoit I, Le May C (2014) Preserved adrenal function in fully PCSK9-deficient subject. Int J Cardiol 176:499–500PubMedGoogle Scholar
  75. 75.
    Gustafsen C, Olsen D, Vilstrup J, Lund S, Reinhardt A, Wellner N, Larsen T, Andersen CBF, Weyer K, Li JP, Seeberger PH, Thirup S, Madsen P, Glerup S (2017) Heparan sulfate proteoglycans present PCSK9 to the LDL receptor. Nat Commun 8:503PubMedPubMedCentralGoogle Scholar
  76. 76.
    Maxwell KN, Breslow JL (2005) Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia. Curr Opin Lipidol 16:167–172PubMedGoogle Scholar
  77. 77.
    Nguyen MA, Kosenko T, Lagace TA (2014) Internalized PCSK9 dissociates from recycling LDL receptors in PCSK9-resistant SV-589 fibroblasts. J Lipid Res 55:266–275PubMedPubMedCentralGoogle Scholar
  78. 78.
    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 282:20799–20803PubMedGoogle Scholar
  79. 79.
    Rudenko G, Henry L, Henderson K, Ichtchenko K, Brown MS, Goldstein JL, Deisenhofer J (2002) Structure of the LDL receptor extracellular domain at endosomal pH. Science 298:2353–2358PubMedGoogle Scholar
  80. 80.
    Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47PubMedGoogle Scholar
  81. 81.
    Goldstein JL, Hobbs HH, Brown MS (2001) Familial hypercholesterol. In: Scriver CR (ed) The metabolic & molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 2863–2913Google Scholar
  82. 82.
    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 54:3345–3357PubMedPubMedCentralGoogle Scholar
  83. 83.
    Romagnuolo R, Scipione CA, Boffa MB, Marcovina SM, Seidah NG, Koschinsky ML (2015) Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. J Biol Chem 290:11649–11662PubMedPubMedCentralGoogle Scholar
  84. 84.
    Nassoury N, Blasiole DA, Tebon Oler A, Benjannet S, Hamelin J, Poupon V, McPherson PS, Attie AD, Prat A, Seidah NG (2007) The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic 8:718–732PubMedGoogle Scholar
  85. 85.
    Jang H-D, Lee SE, Yang J, Lee H-C, Shin D, Lee H, Lee J, Jin S, Kim S, Lee SJ, You J, Park H-W, Nam K-Y, Lee S-H, Park SW, Kim J-S, Kim S-Y, Kwon Y-W, Kwak SH, Yang H-M, Kim H-S (2020) Cyclase-associated protein 1 is a binding partner of proprotein convertase subtilisin/kexin type-9 and is required for the degradation of low-density lipoprotein receptors by proprotein convertase subtilisin/kexin type-9. Eur Heart J 41:239–252PubMedGoogle Scholar
  86. 86.
    Surdo PL, Bottomley MJ, Calzetta A, Settembre EC, Cirillo A, Pandit S, Ni YG, Hubbard B, Sitlani A, Carfi A (2011) Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. EMBO Rep 12:1300–1305PubMedPubMedCentralGoogle Scholar
  87. 87.
    Tveten K, Holla OL, Cameron J, Strom TB, Berge KE, Laerdahl JK, Leren TP (2012) Interaction between the ligand-binding domain of the LDL receptor and the C-terminal domain of PCSK9 is required for PCSK9 to remain bound to the LDL receptor during endosomal acidification. Hum Mol Genet 21:1402–1409PubMedGoogle Scholar
  88. 88.
    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 52:1787–1794PubMedPubMedCentralGoogle Scholar
  89. 89.
    Yamamoto T, Lu C, Ryan RO (2011) A two-step binding model of PCSK9 interaction with the low density lipoprotein receptor. J Biol Chem 286:5464–5470PubMedGoogle Scholar
  90. 90.
    Deng SJ, Alabi A, Gu HM, Adijiang A, Qin S, Zhang DW (2019) Identification of amino acid residues in the ligand binding repeats of LDLR important for PCSK9 binding. J Lipid Res 60:516–527PubMedPubMedCentralGoogle Scholar
  91. 91.
    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 101:76–80PubMedGoogle Scholar
  92. 92.
    Canuel M, Sun X, Asselin M-C, 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:e64145PubMedPubMedCentralGoogle Scholar
  93. 93.
    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 288:10805–10818PubMedPubMedCentralGoogle Scholar
  94. 94.
    Fu T, Guan Y, Xu J, Wang Y (2017) APP, APLP2 and LRP1 interact with PCSK9 but are not required for PCSK9-mediated degradation of the LDLR in vivo. Biochim Biophys Acta 1862:883–889PubMedCentralGoogle Scholar
  95. 95.
    Ly K, Essalmani R, Desjardins R, Seidah NG, Day R (2016) An unbiased mass spectrometry approach identifies Glypican-3 as an interactor of proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDL receptor in hepatocellular carcinoma cells. J Biol ChemGoogle Scholar
  96. 96.
    Sun H, Krauss RM, Chang JT, Teng BB (2018) PCSK9 deficiency reduces atherosclerosis, apolipoprotein B secretion, and endothelial dysfunction. J Lipid Res 59:207–223PubMedGoogle Scholar
  97. 97.
    Huang M, Zhao Z, Cao Q, You X, Wei S, Zhao J, Bai M, Chen Y (2019) PAQR3 modulates blood cholesterol level by facilitating interaction between LDLR and PCSK9. Metabolism 94:88–95PubMedGoogle Scholar
  98. 98.
    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 130:431–441PubMedPubMedCentralGoogle Scholar
  99. 99.
    Le May C, 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 29:684–690PubMedGoogle Scholar
  100. 100.
    Drouin-Chartier JP, Tremblay AJ, Hogue JC, Lemelin V, Lamarche B, Couture P (2018) Plasma PCSK9 correlates with apoB-48-containing triglyceride-rich lipoprotein production in men with insulin resistance. J Lipid Res 59:1501–1509PubMedPubMedCentralGoogle Scholar
  101. 101.
    Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M, Consortium P (eds) (2009) Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 361:2518–2528Google Scholar
  102. 102.
    Emerging Risk Factors C, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J (2009) Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302:412–423Google Scholar
  103. 103.
    Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG (2009) Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301:2331–2339PubMedGoogle Scholar
  104. 104.
    Gencer B, Rigamonti F, Nanchen D, Vuilleumier N, Kern I, Aghlmandi S, Klingenberg R, Raber L, Auer R, Carballo D, Carballo S, Heg D, Windecker S, Luscher TF, Matter CM, Rodondi N, Mach F (2019) Prognostic value of elevated lipoprotein(a) in patients with acute coronary syndromes. Eur J Clin Invest 49:e13117PubMedGoogle Scholar
  105. 105.
    Rader DJ, Mann WA, Cain W, Kraft HG, Usher D, Zech LA, Hoeg JM, Davignon J, Lupien P, Grossman M et al (1995) The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans. J Clin Invest 95:1403–1408PubMedPubMedCentralGoogle Scholar
  106. 106.
    Koschinsky ML, Marcovina SM (2004) Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity. Curr Opin Lipidol 15:167–174PubMedGoogle Scholar
  107. 107.
    Tavori H, Christian D, Minnier J, Plubell D, Shapiro MD, Yeang C, Giunzioni I, Croyal M, Duell PB, Lambert G, Tsimikas S, Fazio S (2016) PCSK9 association with lipoprotein(a). Circ Res 119:29–35PubMedPubMedCentralGoogle Scholar
  108. 108.
    O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, Im K, Lira Pineda A, Wasserman SM, Ceska R, Ezhov MV, Jukema JW, Jensen HK, Tokgozoglu SL, Mach F, Huber K, Sever PS, Keech AC, Pedersen TR, Sabatine MS (2019) Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation 139:1483–1492PubMedGoogle Scholar
  109. 109.
    Ray KK, Vallejo-Vaz AJ, Ginsberg HN, Davidson MH, Louie MJ, Bujas-Bobanovic M, Minini P, Eckel RH, Cannon CP (2019) Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardiovascular events: Pooled analysis of alirocumab phase 3 trials. Atherosclerosis 288:194–202PubMedGoogle Scholar
  110. 110.
    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 283:2363–2372PubMedGoogle Scholar
  111. 111.
    Demers A, Samami S, Lauzier B, Des Rosiers C, Sock ET, Ong H, Mayer G (2015) PCSK9 induces CD36 degradation and affects long-chain fatty acid uptake and triglyceride metabolism in adipocytes and in mouse liver. Arterioscler Thromb Vasc Biol 35:2517–2525PubMedGoogle Scholar
  112. 112.
    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 31:785–791PubMedGoogle Scholar
  113. 113.
    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 51:2611–2618PubMedPubMedCentralGoogle Scholar
  114. 114.
    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 69:1903–1916PubMedGoogle Scholar
  115. 115.
    Wang L, Wang Z, Shi J, Jiang Q, Wang H, Li X, Hao D (2018) Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice. Int J Mol Med 42:2098–2106PubMedPubMedCentralGoogle Scholar
  116. 116.
    Apaijai N, Moisescu DM, Palee S, McSweeney CM, Saiyasit N, Maneechote C, Boonnag C, Chattipakorn N, Chattipakorn SC (2019) Pretreatment with PCSK9 inhibitor protects the brain against cardiac ischemia/reperfusion injury through a reduction of neuronal inflammation and amyloid beta aggregation. J Am Heart Assoc 8:e010838PubMedPubMedCentralGoogle Scholar
  117. 117.
    Jonas MC, Costantini C, Puglielli L (2008) PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep 9:916–922PubMedPubMedCentralGoogle Scholar
  118. 118.
    Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, Goldstein JL (2003) Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci U S A 100:12027–12032PubMedPubMedCentralGoogle Scholar
  119. 119.
    Goldstein JL, Brown MS (2015) A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161:161–172PubMedPubMedCentralGoogle Scholar
  120. 120.
    DeBose-Boyd RA (2008) Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res 18:609–621PubMedPubMedCentralGoogle Scholar
  121. 121.
    Radhakrishnan A, Goldstein JL, McDonald JG, Brown MS (2008) Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance. Cell Metab 8:512–521PubMedPubMedCentralGoogle Scholar
  122. 122.
    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 443:757–768PubMedGoogle Scholar
  123. 123.
    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 59:1697–1705PubMedGoogle Scholar
  124. 124.
    Lin Z, Pan X, Wu F, Ye D, Zhang Y, Wang Y, Jin L, Lian Q, Huang Y, Ding H, Triggle C, Wang K, Li X, Xu A (2015) Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice. Circulation 131:1861–1871PubMedPubMedCentralGoogle Scholar
  125. 125.
    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 284:28885–28895PubMedPubMedCentralGoogle Scholar
  126. 126.
    Dong B, Singh AB, Shende VR, Liu J (2017) Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters. Int J Mol Med 39:749–756PubMedGoogle Scholar
  127. 127.
    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 122:1262–1270PubMedPubMedCentralGoogle Scholar
  128. 128.
    Lai Q, Giralt A, Le May C, Zhang L, Cariou B, Denechaud PD, Fajas L (2017) E2F1 inhibits circulating cholesterol clearance by regulating Pcsk9 expression in the liver. JCI Insight 2Google Scholar
  129. 129.
    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 288:29252–29259PubMedPubMedCentralGoogle Scholar
  130. 130.
    Naeli P, Mirzadeh Azad F, Malakootian M, Seidah NG, Mowla SJ (2017) Post-transcriptional regulation of PCSK9 by miR-191, miR-222, and miR-224. Front Genet 8:189PubMedPubMedCentralGoogle Scholar
  131. 131.
    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 281:30561–30572PubMedGoogle Scholar
  132. 132.
    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. The FEBS journal 275:3480–3493PubMedGoogle Scholar
  133. 133.
    Ben Djoudi Ouadda A, Gauthier MS, Susan-Resiga D, Girard E, Essalmani R, Black M, Marcinkiewicz J, Forget D, Hamelin J, Evagelidis A, Ly K, Day R, Galarneau L, Corbin F, Coulombe B, Caku A, Tagliabracci VS, Seidah NG (2019) Ser-phosphorylation of PCSK9 (proprotein convertase subtilisin-kexin 9) by Fam20C (family with sequence similarity 20, member C) kinase enhances its ability to degrade the LDLR (low-density lipoprotein receptor). Arterioscler Thromb Vasc Biol 39:1996–2013PubMedGoogle Scholar
  134. 134.
    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 55:1505–1514PubMedPubMedCentralGoogle Scholar
  135. 135.
    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 288:8279–8288PubMedPubMedCentralGoogle Scholar
  136. 136.
    Fisher TS, Lo Surdo P, Pandit S, Mattu M, Santoro JC, Wisniewski D, Cummings RT, Calzetta A, Cubbon RM, Fischer PA, Tarachandani A, De Francesco R, 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 282:20502–20512PubMedGoogle Scholar
  137. 137.
    Galvan AM, Chorba JS (2019) Cell-associated heparin-like molecules modulate the ability of LDL to regulate PCSK9 uptake. J Lipid Res 60:71–84PubMedGoogle Scholar
  138. 138.
    Poirier S, Mamarbachi M, Chen WT, Lee AS, Mayer G (2015) GRP94 regulates circulating cholesterol levels through blockade of PCSK9-induced LDLR degradation. Cell Rep 13:2064–2071PubMedGoogle Scholar
  139. 139.
    Mayer G, Poirier S, Seidah NG (2008) Annexin A2 is a C-terminal PCSK9 binding protein that regulates endogenous LDL receptor levels. J Biol Chem 283:31791–31780PubMedGoogle Scholar
  140. 140.
    Wang X, Berry E, Hernandez-Anzaldo S, Sun D, Adijiang A, Li L, Zhang D, Fernandez-Patron C (2015) MMP-2 inhibits PCSK9-induced degradation of the LDL receptor in Hepa1-c1c7 cells. FEBS Lett 589:490–496PubMedGoogle Scholar
  141. 141.
    Spolitu S, Okamoto H, Dai W, Zadroga JA, Wittchen ES, Gromada J, Ozcan L (2019) Hepatic glucagon signaling regulates PCSK9 and low-density lipoprotein cholesterol. Circ Res 124:38–51PubMedPubMedCentralGoogle Scholar
  142. 142.
    Fitchett DH, Hegele RA, Verma S (2015) Cardiology patient page. Statin intolerance. Circulation 131:e389–e391PubMedGoogle Scholar
  143. 143.
    Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, van Heyningen C, Soutar AK (2005) Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol 25:2654–2660PubMedGoogle Scholar
  144. 144.
    Benn M, Tybjaerg-Hansen A, Nordestgaard BG (2019) Low LDL cholesterol by PCSK9 variation reduces cardiovascular mortality. J Am Coll Cardiol 73:3102–3114PubMedGoogle Scholar
  145. 145.
    Leander K, Malarstig A, Van’t Hooft FM, Hyde C, Hellenius ML, Troutt JS, Konrad RJ, Ohrvik J, Hamsten A, de Faire U (2016) Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) predicts future risk of cardiovascular events independently of established risk factors. Circulation 133:1230–1239PubMedGoogle Scholar
  146. 146.
    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 125:894–901PubMedGoogle Scholar
  147. 147.
    Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ, Investigators OLT (2015) Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 372:1489–1499PubMedGoogle Scholar
  148. 148.
    Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Lecorps G, Mahaffey KW, Moryusef A, Pordy R, Quintero K, Roe MT, Sasiela WJ, Tamby JF, Tricoci P, White HD, Zeiher AM, Committees OO, Investigators (2018) Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 379:2097–2107PubMedPubMedCentralGoogle Scholar
  149. 149.
    Sabatine MS, De Ferrari GM, Giugliano RP, Huber K, Lewis BS, Ferreira J, Kuder JF, Murphy SA, Wiviott SD, Kurtz CE, Honarpour N, Keech AC, Sever PS, Pedersen TR (2018) Clinical benefit of evolocumab by severity and extent of coronary artery disease: an analysis from FOURIER. Circulation 138:756–766PubMedPubMedCentralGoogle Scholar
  150. 150.
    Ray KK, Stoekenbroek RM, Kallend D, Leiter LA, Landmesser U, Wright RS, Wijngaard P, Kastelein JJP (2018) Effect of an siRNA therapeutic targeting PCSK9 on atherogenic lipoproteins. Circulation 138:1304–1316PubMedGoogle Scholar
  151. 151.
    Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RP, Turner T, Visseren FL, Wijngaard P, Wright RS, Kastelein JJ (2017) Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 376:1430–1440PubMedGoogle Scholar
  152. 152.
    Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA, Open-Label Study of Long-Term Evaluation against, L. D. L. C. I (2015) Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 372:1500–1509PubMedGoogle Scholar
  153. 153.
    Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM, for the, O. C. I. I. I (2015) Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart JGoogle Scholar
  154. 154.
    Kazi DS, Moran AE, Coxson PG, Penko J, Ollendorf DA, Pearson SD, Tice JA, Guzman D, Bibbins-Domingo K (2016) Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA 316:743–753PubMedGoogle Scholar
  155. 155.
    Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G, Linsley PS (2003) Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol 21:635–637PubMedGoogle Scholar
  156. 156.
    Pecot CV, Calin GA, Coleman RL, Lopez-Berestein G, Sood AK (2011) RNA interference in the clinic: challenges and future directions. Nat Rev Cancer 11:59–67PubMedGoogle Scholar
  157. 157.
    Adorni MP, Ruscica M, Ferri N, Bernini F, Zimetti F (2019) Proprotein convertase subtilisin/kexin type 9, brain cholesterol homeostasis and potential implication for alzheimer’s disease. Front Aging Neurosci 11:120PubMedPubMedCentralGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Departments of Pediatrics, Group on the Molecular and Cell Biology of LipidsUniversity of AlbertaEdmontonCanada
  2. 2.Institute of Lipid Metabolism and Atherosclerosis, Innovative Drug Research Centre, School of PharmacyWeifang Medical UniversityWeifangChina
  3. 3.Department of Orthopedics, the sixth affiliated hospital (Qingyuan People’s Hospital)Guangzhou Medical UniversityQingyuanChina

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