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THE ROLE OF PCSK9 IN THE REGULATION OF LIPOPROTEIN TRANSPORT (REVIEW)

DOI: https://doi.org/10.29296/25877313-2021-01-04
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Issue: 
1
Year: 
2021

A.M. Chaulin Post-graduate Student, Doctor of Clinical Laboratory Diagnostics, Samara Regional Cardiology Dispensary; Samara State Medical University(Samara) E-mail: alekseymichailovich22976@gmail.com D.V. Duplyakov Dr.Sc. (Med.), Professor, Samara Regional Cardiology Dispensary; Samara State Medical University(Samara)

The article summarizes the role of the new type 9 subtilisin-Kexin protein convertase (PCSK9) in the regulation of lipoprotein transport. Impaired transport, characterized by excessive serum cholesterol and low-density atherogenic lipoproteins, is a key risk factor for the development of athero-sclerosis and cardiovascular diseases. Due to the fact that PCSK9 causes degradation of low-density lipoprotein receptors and increases the level of atherogenic low-density lipoproteins, PCSK9 has become a new target for the development of therapeutic drugs for the treatment and prevention of cardiovascular diseases. At the same time, review articles on PCSK9 do not pay enough attention to ITS additional role in regulating lipoprotein transport. In this regard, this review discusses the effects of PCSK9 on other receptors involved in lipid metabolism, further study of which is of great practical importance in the future.
Keywords: 
PCSK9
regulation
transport of lipoproteins
low-density lipoproteins
low-density lipoprotein receptors
very low-density lipoprotein receptors
apolipopro-tein E receptor
lectin-like oxidized low-density lipoproteins receptor-1
cluster of differentiation 36

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References: 
  1. Seidah N.G., Benjannet S., Wickham L., et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proceedings of the National Academy of Sciences of the United States of America. 2003; 100(3): 928-933. doi: 10.1073/pnas.0335507100
  2. Abifadel M., Varret M., Rabes J.P., et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics. 2003; 34 (2): 154-156. DOI: 10.1038/ng1161
  3. Chaulin A.M., Dupljakov D.V. PCSK-9: sovremennye predstavlenija o biologicheskoj roli i vozmozhnosti ispol'zovanija v kachestve diagnosticheskogo markera serdechno-sosudistyh zabolevanij. Chast' 1. Kardiologija: novosti, mnenija, obuchenie. 2019; 7 (2): 45–57. doi: 10.24411/2309-1908-2019-12005. Chaulin A.M., Duplyakov D.V. PCSK-9: modern views about biological role and possibilities of use as a diagnostic marker for cardiovascular diseases. Part 1. Kardiologiya: novosti, mneniya, obuchenie [Cardiology: News, Opinions, Training]. 2019; 7 (2): 45–57. doi: 10.24411/2309-1908-2019-12005. (in Russian)
  4. Chaulin A.M., Dupljakov D.V. PCSK-9: sovremennye predstavlenija o biologicheskoj roli i vozmozhnosti ispol'zovanija v kachestve diagnosticheskogo markera serdechno-sosudistyh zabolevanij. Chast' 2. Kardiologija: novosti, mnenija, obuchenie. ‒2019; 7 (4): 24–35. doi: 10.24411/2309-1908-2019-14004. Chaulin A.M., Duplyakov D.V. PCSK-9: modern views about biological role and possibilities of use as a diagnostic marker for cardiovascular diseases. Part 2. Kardiologiya: novosti, mneniya, obuchenie [Cardiology: News, Opinions, Training]. 2019; 7 (4): 24–35. doi: 10.24411/2309-1908-2019-14004 (in Russian).
  5. Liu MH. Antihyperlipidemic therapies targeting PCSK9: Novel therapeutic agents for lowering low-density lipoprotein cholesterol. Int. J. Cardiol. 2015; 195: 212-214. doi:10.1016/j.ijcard.2015.05.150.
  6. Tavori H., Fan D., Blakemore J.L., et al. Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation. Circulation. 2013; 127(24): 2403-2413. doi:10.1161/CIRCULATIONAHA.113.001592
  7. Ogura M. PCSK9 inhibition in the management of familial hypercholesterolemia. J Cardiol. 2018; 71(1): 1-7. doi:10.1016/j.jjcc.2017.07.002
  8. Bonaca M.P., Nault P., Giugliano R.P., et al. Low-Density Li-poprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation. 2018; 137(4): 338-350. doi:10.1161/CIRCULA-TIONAHA.117.032235
  9. Toth P.P., Worthy G., Gandra S.R., et al. Systematic Review and Network Meta-Analysis on the Efficacy of Evolocumab and Other Therapies for the Management of Lipid Levels in Hyperlipidemia. J Am Heart Assoc. 2017; 6(10): e005367. doi:10.1161/JAHA.116.005367
  10. Poirier S., Mayer G., Benjannet S., et al. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J. Biol. Chem. 2008; 283(4): 2363-2372. doi:10.1074/jbc.M708098200
  11. Shan L., Pang L., Zhang R., et al. PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide. Biochem Biophys Res Commun. 2008; 375(1): 69-73. doi:10.1016/j.bbrc.2008.07.106
  12. Roubtsova A., Munkonda M.N., Awan Z., et al. Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler. Thromb. Vasc. Biol. 2011; 31(4): 785-791. doi:10.1161/ATVBAHA.110.220988
  13. Roubtsova A., Chamberland A., Marcinkiewicz J., et al. PCSK9 deficiency unmasks a sex- and tissue-specific subcellular distribution of the LDL and VLDL receptors in mice. J. Lipid. Res. 2015; 56(11): 2133-2142. doi:10.1194/jlr.M061952
  14. Smolina M.O., Benimetskaja K.S., Ragino Ju.I., Voevoda M.I. PCSK9: novye pobedy i novye gorizonty. Ateroskleroz. 2018; 14(3): 70-77. doi: 10.15372/ATER20180311. Smolina M.O., Benimetskaya K.S., Ragino Yu.I., Voevoda M.I. PCSK9: new victory and horizons. Ateroscleroz. 2018; 14(3): 70-77. doi: 10.15372/ATER20180311 (In Russian)
  15. Popova A.B., Nozadze D.N., Sergienko I.V. Rol' PCSK9 v geneze razvitija serdechno-sosudistyh zabolevanij. Ateros-kleroz i dislipidemii. 2016; 2: 5-14. Popova A.B., Nozadze D.N., Sergienko I.V. The role of PCSK9 in coronary vascular disease development. Ateroskleroz i Dislipidemii. The Journal of Atherosclerosis and Dyslipidemias. 2016; 2: 5-14 (In Russian).
  16. Piper D.E., Jackson S., Liu Q., et al. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure. 2007; 15(5): 545-552. doi:10.1016/j.str.2007.04.004
  17. McNutt M.C., Lagace T.A., Horton J.D. Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells. The Journal of Biological Chemistry. 2007 Jul; 282(29): 20799-20803. doi: 10.1074/jbc.c700095200.
  18. Kosenko T., Golder M., Leblond G., et al. Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation. J. Biol. Chem. 2013; 288(12): 8279-8288. doi: 10.1074/jbc.M112.421370
  19. Zhang D.W., Lagace T.A., Garuti R., et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J. Biol. Chem. 2007; 282(25): 18602-18612. doi:10.1074/jbc.M702027200
  20. McNutt M.C., Kwon H.J., Chen C., Chen J.R., Horton J.D., Lagace T.A. Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J. Biol. Chem. 2009; 284(16): 10561-10570. doi:10.1074/jbc.M808802200
  21. Manniello M., Pisano M. Alirocumab (Praluent): First in the New Class of PCSK9 Inhibitors. P T. 2016; 41(1): 28-53. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699483/
  22. Kasichayanula S., Grover A., Emery M.G., et al. Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor. Clin Pharmacokinet. 2018 Jul; 57(7): 769-779. doi: 10.1007/s40262-017-0620-7.
  23. Soininen K., Niemi M., Kilkki E., et al. Muscle symptoms associated with statins: a series of twenty patients. Basic Clin Pharmacol Toxicol. 2006; 98(1): 51-54. doi:10.1111/j.1742-7843.2006.pto_193.x
  24. Draeger A., Monastyrskaya K., Mohaupt M., et al. Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia. J Pathol. 2006; 210(1): 94-102. doi:10.1002/path.2018
  25. Leiter L.A., Teoh H., Kallend D., et al. Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial. Diabetes Care. 2019; 42(1): 173-176. doi: 10.2337/dc18-1491.
  26. van Poelgeest E.P., Hodges M.R., Moerland M., et al. Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first-in-human randomized, placebo-controlled trial. Br. J. Clin Pharmacol. 2015; 80(6): 1350-1361. doi:10.1111/bcp.12738
  27. Lintner N.G., McClure K.F., Petersen D., et al. Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biol. 2017; 15(3): e2001882. doi:10.1371/journal.pbio.2001882
  28. Alghamdi R.H., O'Reilly P., Lu C., Gomes J., Lagace T.A., Basak A. LDL-R promoting activity of peptides derived from human PCSK9 catalytic domain (153-421): design, synthesis and biochemical evaluation. Eur. J. Med. Chem. 2015; 92: 890-907. doi:10.1016/j.ejmech.2015.01.022
  29. Mitchell T., Chao G., Sitkoff D., et al. Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. J. Pharmacol. Exp. Ther. 2014; 350(2): 412-424. doi:10.1124/jpet.114.214221
  30. Landlinger C., Pouwer M.G., Juno C., et al. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. Eur. Heart. J. 2017; 38(32): 2499-2507. doi: 10.1093/eurheartj/ehx260.
  31. Nishikido T., Ray K.K. Non-antibody Approaches to Proprotein Convertase Subtilisin Kexin 9 Inhibition: siRNA, Antisense Oligonucleotides, Adnectins, Vaccination, and New Attempts at Small-Molecule Inhibitors Based on New Discoveries. Front. Cardiovasc. Med. 2019; 5: 199. doi: 10.3389/fcvm.2018.00199.
  32. Pothineni N.V.K., Karathanasis S.K., Ding Z., et al. LOX-1 in atherosclerosis and myocardial ischemia: biology, genetics, and modulation. J. Am. Coll. Cardiol. 2017; 69(22): 2759-2768. https://doi.org/10.1016/j.jacc.2017.04.010
  33. Xu S., Ogura S., Chen J., Little P.J., Moss J., Liu P. LOX-1 in atherosclerosis: biological functions and pharmacological modifiers. Cell Mol Life Sci. 2013; 70(16): 2859-2872. doi:10.1007/s00018-012-1194-z
  34. Ding Z., Liu S., Wang X., et al. Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovasc Res. 2015; 107(4): 556-567. doi:10.1093/cvr/cvv178
  35. Yokota C., Sawamura T., Watanabe M., et al. High Levels of Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 in Acute Stroke: An Age- and Sex-Matched Cross-Sectional Study. J. Atheroscler. Thromb. 2016; 23(10): 1222-1226. doi:10.5551/jat.32466
  36. Ding Z., Pothineni N.V.K., Goel A., Lüscher T.F., Mehta J.L. PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1. Cardiovasc Res. 2020; 116(5): 908-915. doi:10.1093/cvr/cvz313
  37. May P., Woldt E., Matz R.L., et al. The LDL receptor-related protein (LRP) family: an old family of proteins with new physiological functions. Ann Med. 2007; 39(3): 219-228. doi:10.1080/07853890701214881
  38. Gardai S.J., McPhillips K.A., Frasch S.C., et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell. 2005; 123(2): 321-334. doi:10.1016/j.cell.2005.08.032
  39. Canuel M., Sun X., Asselin M.C., et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1). PLoS One. 2013; 8(5): e64145. Published 2013 May 13. doi:10.1371/journal.pone.0064145
  40. Langlois B., Emonard H., Martiny L., et al. Implications multiples du récepteur LRP-1 dans la progression tumorale [Multiple involvements of LRP-1 receptor in tumor progression]. Pathol Biol (Paris). 2009; 57(7-8): 548-554. doi:10.1016/j.patbio.2008.07.015
  41. Sun X., Essalmani R., Day R., et al. Proprotein convertase subtilisin/kexin type 9 deficiency reduces melanoma metastasis in liver. Neoplasia. 2012; 14(12): 1122-1131. doi:10.1593/neo.121252
  42. Leblond F., Seidah N.G., Précourt L.P., Delvin E., Domingu-
  43. ez M., Levy E. Regulation of the proprotein convertase subtilisin/kexin type 9 in intestinal epithelial cells. Am. J. Physiol. Gastrointest. Liver. Physiol. 2009; 296(4): G805-G815. doi:10.1152/ajpgi.90424.2008
  44. Levy E., Ben Djoudi Ouadda A., Spahis S., et al. PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells. Atherosclerosis. 2013; 227(2): 297-306. doi:10.1016/j.atherosclerosis.2013.01.023
  45. Demers A., Samami S., Lauzier B., et al. PCSK9 Induces CD36 Degradation and Affects Long-Chain Fatty Acid Uptake and Triglyceride Metabolism in Adipocytes and in Mouse Liver. Arterioscler Thromb Vasc Biol. 2015; 35(12): 2517-2525. doi:10.1161/ATVBAHA.115.306032
  46. Park Y.M. CD36, a scavenger receptor implicated in atherosclerosis. Exp. Mol. Med. 2014; 46(6): e99. doi:10.1038/emm.2014.38
  47. Lebeau P.F., Byun J.H., Platko K., et al. Pcsk9 knockout exacerbates diet-induced non-alcoholic steatohepatitis, fibrosis and liver injury in mice. JHEP Rep. 2019; 1(6): 418-429. doi:10.1016/j.jhepr.2019.10.009
  48. Kysenius K., Muggalla P., Mätlik K., et al. PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling. Cell. Mol. Life Sci. 2012; 69(11): 1903-1916. doi:10.1007/s00018-012-0977-6
  49. Beffert U., Nematollah Farsian F., Masiulis I., et al. ApoE receptor 2 controls neuronal survival in the adult brain. Curr Biol. 2006; 16(24): 2446-2452. doi:10.1016/j.cub.2006.10.029
  50. Ce O., Rs P., Ab W., et al. Potential Link Between Proprotein Convertase Subtilisin/Kexin Type 9 and Alzheimer's Disease. Int. J. Biomed. Investig. 2018; 1(1):106. doi:10.31531/2581-4745.1000106