PCSK9 in extrahepatic tissues: What can we expect from its inhibition?

PCSK9 inhibition beyond the liver

Angela Pirillo
Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy
Lale Tokgözoğlu
Hacettepe University Medical Faculty, Department of Cardiology, Ankara, Turkey
Alberico L. Catapano
IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy and Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy


Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that belongs to the serine protease family and plays a key role in regulating low-density lipoprotein cholesterol (LDL-C) levels in the blood. PCSK9 binds to the LDL receptor (LDLR), targeting it for degradation, resulting in an increase in circulating LDL-C levels. Loss-of-function mutations in the PCSK9 gene are associated with lower LDL-C levels and lower cardiovascular risk; in contrast, gain-of-function mutations are a cause of familial hypercholesterolaemia. The identification of PCSK9 as a pharmacological target led to the development of inhibitors for the treatment of hypercholesterolaemia. To date, the monoclonal antibodies evolocumab and alirocumab (which target plasma PCSK9) and the small-interfering RNA inclisiran (which targets hepatic PCSK9 mRNA) have been approved for the treatment of hypercholesterolaemia. Although hepatic PCSK9 plays a central role in regulating plasma LDL-C levels, this protein is also expressed in other tissues, including the brain, pancreas, heart, kidney, intestine and adipose tissue. In extrahepatic tissues, the functions of PCSK9 are both dependent and independent of LDLR and not necessarily harmful. For this reason, it is essential to uncover any potentially harmful effects of therapies that inhibit PCSK9, beyond their known LDL-C-lowering and CV risk-reducing effects.



  1. Seidah NG, Prat A. The Multifaceted Biology of PCSK9. Endocr Rev 2022; 43:558-82. https://doi.org/10.1210/endrev/bnab035
  2. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34:154-6. https://doi.org/10.1038/ng1161
  3. Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005; 37:161-5. https://doi.org/10.1038/ng1509
  4. Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264-72. https://doi.org/10.1056/NEJMoa054013
  5. Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006; 79:514-23. https://doi.org/10.1086/507488
  6. Humphries SE, Neely RD, Whittall RA, et al. Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9. Clin Chem 2009; 55:2153-61. https://doi.org/10.1373/clinchem.2009.129759
  7. Mabuchi H, Nohara A, Noguchi T, et al. Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation. Atherosclerosis 2014; 236:54-61. https://doi.org/10.1016/j.atherosclerosis.2014.06.005
  8. Noguchi T, Katsuda S, Kawashiri MA, et al. The E32K variant of PCSK9 exacerbates the phenotype of familial hypercholesterolaemia by increasing PCSK9 function and concentration in the circulation. Atherosclerosis 2010; 210:166-72. https://doi.org/10.1016/j.atherosclerosis.2009.11.018
  9. Sanchez-Hernandez RM, Di Taranto MD, Benito-Vicente A, et al. The Arg499His gain-of-function mutation in the C-terminal domain of PCSK9. Atherosclerosis 2019; 289:162-72. https://doi.org/10.1016/j.atherosclerosis.2019.08.020
  10. Sarkar SK, Matyas A, Asikhia I, et al. Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding. Front Physiol 2022; 13:960272. https://doi.org/10.3389/fphys.2022.960272
  11. Huijgen R, Blom DJ, Hartgers ML, et al. Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town. Arterioscler Thromb Vasc Biol 2021; 41:934-43. https://doi.org/10.1161/ATVBAHA.120.314482
  12. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376:1713-22. https://doi.org/10.1056/NEJMoa1615664
  13. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379:2097-107. https://doi.org/10.1056/NEJMoa1801174
  14. O'Connell EM, Lohoff FW. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in the Brain and Relevance for Neuropsychiatric Disorders. Front Neurosci 2020; 14:609. https://doi.org/10.3389/fnins.2020.00609
  15. Dietschy JM. Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol Chem 2009; 390:287-93. https://doi.org/10.1515/BC.2009.035
  16. 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; 283:2363-72. https://doi.org/10.1074/jbc.M708098200
  17. Chen YQ, Troutt JS, Konrad RJ. PCSK9 is present in human cerebrospinal fluid and is maintained at remarkably constant concentrations throughout the course of the day. Lipids 2014; 49:445-55. https://doi.org/10.1007/s11745-014-3895-6
  18. Garcia-Morales V, Gonzalez-Acedo A, Melguizo-Rodriguez L, et al. Current Understanding of the Physiopathology, Diagnosis and Therapeutic Approach to Alzheimer's Disease. Biomedicines 2021; 9. https://doi.org/10.3390/biomedicines9121910
  19. Bell AS, Wagner J, Rosoff DB, Lohoff FW. Proprotein convertase subtilisin/kexin type 9 (PCSK9) in the central nervous system. Neurosci Biobehav Rev 2023; 149:105155. https://doi.org/10.1016/j.neubiorev.2023.105155
  20. Reed B, Villeneuve S, Mack W, et al. Associations between serum cholesterol levels and cerebral amyloidosis. JAMA Neurol 2014; 71:195-200. https://doi.org/10.1001/jamaneurol.2013.5390
  21. Storck SE, Meister S, Nahrath J, et al. Endothelial LRP1 transports amyloid-beta(1-42) across the blood-brain barrier. J Clin Invest 2016; 126:123-36. https://doi.org/10.1172/JCI81108
  22. Li J, Li M, Ge Y, et al. beta-amyloid protein induces mitophagy-dependent ferroptosis through the CD36/PINK/PARKIN pathway leading to blood-brain barrier destruction in Alzheimer's disease. Cell Biosci 2022; 12:69. https://doi.org/10.1186/s13578-022-00807-5
  23. Mazura AD, Ohler A, Storck SE, et al. PCSK9 acts as a key regulator of Abeta clearance across the blood-brain barrier. Cell Mol Life Sci 2022; 79:212. https://doi.org/10.1007/s00018-022-04237-x
  24. Kysenius K, Muggalla P, Matlik K, et al. PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling. Cell Mol Life Sci 2012; 69:1903-16. https://doi.org/10.1007/s00018-012-0977-6
  25. Giugliano RP, Mach F, Zavitz K, et al. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med 2017; 377:633-43. https://doi.org/10.1056/NEJMoa1701131
  26. Robinson JG, Rosenson RS, Farnier M, et al. Safety of Very Low Low-Density Lipoprotein Cholesterol Levels With Alirocumab: Pooled Data From Randomized Trials. J Am Coll Cardiol 2017; 69:471-82. https://doi.org/10.1016/j.jacc.2016.11.037
  27. Guedeney P, Giustino G, Sorrentino S, et al. Efficacy and safety of alirocumab and evolocumab: a systematic review and meta-analysis of randomized controlled trials. Eur Heart J 2019. https://doi.org/10.1093/eurheartj/ehz430
  28. Gencer B, Mach F, Guo J, et al. Cognition After Lowering LDL-Cholesterol With Evolocumab. J Am Coll Cardiol 2020; 75:2283-93. https://doi.org/10.1016/j.jacc.2020.03.039
  29. Ying H, Wang J, Shen Z, et al. Impact of Lowering Low-Density Lipoprotein Cholesterol with Contemporary Lipid-Lowering Medicines on Cognitive Function: A Systematic Review and Meta-Analysis. Cardiovasc Drugs Ther 2021; 35:153-66. https://doi.org/10.1007/s10557-020-07045-2
  30. Gaba P, O'Donoghue ML, Park JG, et al. Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE. Circulation 2023; 147:1192-203. https://doi.org/10.1161/CIRCULATIONAHA.122.063399
  31. Mefford MT, Rosenson RS, Cushman M, et al. PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment: Reasons for Geographic and Racial Differences in Stroke Study (REGARDS). Circulation 2018; 137:1260-9. https://doi.org/10.1161/CIRCULATIONAHA.117.029785
  32. Rosoff DB, Bell AS, Jung J, et al. Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function. J Am Coll Cardiol 2022; 80:653-62. https://doi.org/10.1016/j.jacc.2022.05.041
  33. Bell AS, Rosoff DB, Mavromatis LA, et al. Comparing the Relationships of Genetically Proxied PCSK9 Inhibition With Mood Disorders, Cognition, and Dementia Between Men and Women: A Drug-Target Mendelian Randomization Study. J Am Heart Assoc 2022; 11:e026122. https://doi.org/10.1161/JAHA.122.026122
  34. Evans MA, Golomb BA. Statin-associated adverse cognitive effects: survey results from 171 patients. Pharmacotherapy 2009; 29:800-11. https://doi.org/10.1592/phco.29.7.800
  35. Parker BA, Polk DM, Rabdiya V, et al. Changes in Memory Function and Neuronal Activation Associated with Atorvastatin Therapy. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 2010; 30:625-. https://doi.org/10.1592/phco.30.6.625
  36. Williams DM, Finan C, Schmidt AF, et al. Lipid lowering and Alzheimer disease risk: A mendelian randomization study. Ann Neurol 2020; 87:30-9. https://doi.org/10.1002/ana.25642
  37. Gouverneur A, Sanchez-Pena P, Veyrac G, et al. Neurocognitive Disorders Associated with PCSK9 Inhibitors: a Pharmacovigilance Disproportionality Analysis. Cardiovasc Drugs Ther 2023; 37:271-6. https://doi.org/10.1007/s10557-021-07242-7
  38. Perego C, Da Dalt L, Pirillo A, et al. Cholesterol metabolism, pancreatic beta-cell function and diabetes. Biochim Biophys Acta Mol Basis Dis 2019; 1865:2149-56. https://doi.org/10.1016/j.bbadis.2019.04.012
  39. Casula M, Mozzanica F, Scotti L, et al. Statin use and risk of new-onset diabetes: a meta-analysis of observational studies. Nutr Metab Cardiovasc Dis 2017; 27:396-406. https://doi.org/10.1016/j.numecd.2017.03.001
  40. Tcheoubi SER, Akpovi CD, Coppee F, et al. Molecular and cellular biology of PCSK9: impact on glucose homeostasis. J Drug Target 2022; 30:948-60. https://doi.org/10.1080/1061186X.2022.2092622
  41. Schmidt AF, Swerdlow DI, Holmes MV, et al. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol 2017; 5:97-105. https://doi.org/10.1016/S2213-8587(16)30396-5
  42. Lotta LA, Sharp SJ, Burgess S, et al. Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis. JAMA 2016; 316:1383-91. https://doi.org/10.1001/jama.2016.14568
  43. Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016; 375:2144-53. https://doi.org/10.1056/NEJMoa1604304
  44. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 2017; 5:941-50. https://doi.org/10.1016/S2213-8587(17)30313-3
  45. O'Donoghue ML, Giugliano RP, Wiviott SD, et al. Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease. Circulation 2022; 146:1109-19. https://doi.org/10.1161/CIRCULATIONAHA.122.061620
  46. Da Dalt L, Ruscica M, Bonacina F, et al. PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor. Eur Heart J 2019; 40:357-68. https://doi.org/10.1093/eurheartj/ehy357
  47. Peyot ML, Roubtsova A, Lussier R, et al. Substantial PCSK9 inactivation in beta-cells does not modify glucose homeostasis or insulin secretion in mice. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:158968. https://doi.org/10.1016/j.bbalip.2021.158968
  48. Marku A, Da Dalt L, Galli A, et al. Pancreatic PCSK9 controls the organization of the beta-cell secretory pathway via LDLR-cholesterol axis. Metabolism 2022; 136:155291. https://doi.org/10.1016/j.metabol.2022.155291
  49. Schluter KD, Wolf A, Weber M, et al. Oxidized low-density lipoprotein (oxLDL) affects load-free cell shortening of cardiomyocytes in a proprotein convertase subtilisin/kexin 9 (PCSK9)-dependent way. Basic Res Cardiol 2017; 112:63. https://doi.org/10.1007/s00395-017-0650-1
  50. Ding Z, Wang X, Liu S, et al. PCSK9 expression in the ischaemic heart and its relationship to infarct size, cardiac function, and development of autophagy. Cardiovasc Res 2018; 114:1738-51. https://doi.org/10.1093/cvr/cvy128
  51. Yang CL, Zeng YD, Hu ZX, Liang H. PCSK9 promotes the secretion of pro-inflammatory cytokines by macrophages to aggravate H/R-induced cardiomyocyte injury via activating NF-kappaB signalling. Gen Physiol Biophys 2020; 39:123-34. http://dx.doi.org/10.4149/gpb_2019057
  52. Wolf A, Kutsche HS, Schreckenberg R, et al. Autocrine effects of PCSK9 on cardiomyocytes. Basic Res Cardiol 2020; 115:65. https://doi.org/10.1007/s00395-020-00824-w
  53. Huang G, Bao H, Zhan P, et al. PCSK9 regulates myocardial ischemia–reperfusion injury through parkin/pink1-mediated autophagy pathway. Molecular & Cellular Toxicology 2023. https://doi.org/10.1007/s13273-023-00352-3
  54. Wang F, Li M, Zhang A, et al. PCSK9 Modulates Macrophage Polarization-Mediated Ventricular Remodeling after Myocardial Infarction. J Immunol Res 2022; 2022:7685796. https://doi.org/10.1155/2022/7685796
  55. Huang G, Lu X, Duan Z, et al. PCSK9 Knockdown Can Improve Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy. Cardiovascular Toxicology 2022; 22:951-61. https://doi.org/10.1007/s12012-022-09771-5
  56. Palee S, McSweeney CM, Maneechote C, et al. PCSK9 inhibitor improves cardiac function and reduces infarct size in rats with ischaemia/reperfusion injury: Benefits beyond lipid-lowering effects. J Cell Mol Med 2019; 23:7310-9. https://doi.org/10.1111/jcmm.14586
  57. Zeng C, Duan F, Hu J, et al. NLRP3 inflammasome-mediated pyroptosis contributes to the pathogenesis of non-ischemic dilated cardiomyopathy. Redox Biol 2020; 34:101523. https://doi.org/10.1016/j.redox.2020.101523
  58. Wang X, Li X, Liu S, et al. PCSK9 regulates pyroptosis via mtDNA damage in chronic myocardial ischemia. Basic Res Cardiol 2020; 115:66. https://doi.org/10.1007/s00395-020-00832-w
  59. Da Dalt L, Castiglioni L, Baragetti A, et al. PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction. Eur Heart J 2021; 42:3078-90. https://doi.org/10.1093/eurheartj/ehab431
  60. Laudette M, Lindbom M, Arif M, et al. Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function. Cardiovasc Res 2023; 119:1537-52. https://doi.org/10.1093/cvr/cvad041
  61. Baragetti A, Balzarotti G, Grigore L, et al. PCSK9 deficiency results in increased ectopic fat accumulation in experimental models and in humans. Eur J Prev Cardiol 2017; 24:1870-7. https://doi.org/10.1177/2047487317724342
  62. Trudso LC, Ghouse J, Ahlberg G, et al. Association of PCSK9 Loss-of-Function Variants With Risk of Heart Failure. JAMA Cardiol 2023; 8:159-66. https://doi.org/10.1001/jamacardio.2022.4798
  63. White HD, Steg PG, Szarek M, et al. Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial. Eur Heart J 2019; 40:2801-9. https://doi.org/10.1093/eurheartj/ehz299
  64. Wiviott SD, Giugliano RP, Morrow DA, et al. Effect of Evolocumab on Type and Size of Subsequent Myocardial Infarction: A Prespecified Analysis of the FOURIER Randomized Clinical Trial. JAMA Cardiol 2020; 5:787-93. https://doi.org/10.1001/jamacardio.2020.0764
  65. Asbeutah AAA, Asbeutah SA, Abu-Assi MA. A Meta-Analysis of Cardiovascular Outcomes in Patients With Hypercholesterolemia Treated With Inclisiran. Am J Cardiol 2020; 128:218-9. https://doi.org/10.1016/j.amjcard.2020.05.024
  66. White HD, Schwartz GG, Szarek M, et al. Alirocumab after acute coronary syndrome in patients with a history of heart failure. Eur Heart J 2022; 43:1554-65. https://doi.org/10.1093/eurheartj/ehab804
  67. Niessner A, Drexel H. PCSK9 inhibition in patients with heart failure: neutral or harmful intervention? Eur Heart J 2022; 43:1566-8. https://doi.org/10.1093/eurheartj/ehab913
  68. Sharotri V, Collier DM, Olson DR, et al. Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). J Biol Chem 2012; 287:19266-74. https://doi.org/10.1074/jbc.M112.363382
  69. Kwakernaak AJ, Lambert G, Slagman MC, et al. Proprotein convertase subtilisin-kexin type 9 is elevated in proteinuric subjects: relationship with lipoprotein response to antiproteinuric treatment. Atherosclerosis 2013; 226:459-65. https://doi.org/10.1016/j.atherosclerosis.2012.11.009
  70. Jin K, Park BS, Kim YW, Vaziri ND. Plasma PCSK9 in nephrotic syndrome and in peritoneal dialysis: a cross-sectional study. Am J Kidney Dis 2014; 63:584-9. https://doi.org/10.1053/j.ajkd.2013.10.042
  71. Haas ME, Levenson AE, Sun X, et al. The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia. Circulation 2016; 134:61-72. https://doi.org/10.1161/CIRCULATIONAHA.115.020912
  72. Konarzewski M, Szolkiewicz M, Sucajtys-Szulc E, et al. Elevated circulating PCSK-9 concentration in renal failure patients is corrected by renal replacement therapy. Am J Nephrol 2014; 40:157-63. https://doi.org/10.1159/000365935
  73. Abujrad H, Mayne J, Ruzicka M, et al. Chronic kidney disease on hemodialysis is associated with decreased serum PCSK9 levels. Atherosclerosis 2014; 233:123-9. https://doi.org/10.1016/j.atherosclerosis.2013.12.030
  74. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009; 360:1395-407. https://doi.org/10.1056/NEJMoa0810177
  75. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238-48. https://doi.org/10.1056/NEJMoa043545
  76. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011; 377:2181-92. https://doi.org/10.1016/S0140-6736(11)60739-3
  77. Igweonu-Nwakile EO, Ali S, Paul S, et al. A Systematic Review on the Safety and Efficacy of PCSK9 Inhibitors in Lowering Cardiovascular Risks in Patients With Chronic Kidney Disease. Cureus 2022; 14:e29140. https://doi.org/10.7759/cureus.29140
  78. Charytan DM, Sabatine MS, Pedersen TR, et al. Efficacy and Safety of Evolocumab in Chronic Kidney Disease in the FOURIER Trial. J Am Coll Cardiol 2019; 73:2961-70. https://doi.org/10.1016/j.jacc.2019.03.513
  79. Toth PP, Dwyer JP, Cannon CP, et al. Efficacy and safety of lipid lowering by alirocumab in chronic kidney disease. Kidney Int 2018; 93:1397-408. https://doi.org/10.1016/j.kint.2017.12.011
  80. Tunon J, Steg PG, Bhatt DL, et al. Effect of alirocumab on major adverse cardiovascular events according to renal function in patients with a recent acute coronary syndrome: prespecified analysis from the ODYSSEY OUTCOMES randomized clinical trial. Eur Heart J 2020; 41:4114-23. https://doi.org/10.1093/eurheartj/ehaa498
  81. Duan Y, Gong K, Xu S, et al. Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics. Signal Transduction and Targeted Therapy 2022; 7:265. https://doi.org/10.1038/s41392-022-01125-5
  82. Le May C, Kourimate S, Langhi C, et al. Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. Arterioscler Thromb Vasc Biol 2009; 29:684-90. https://doi.org/10.1161/ATVBAHA.108.181586
  83. Moreau F, Thedrez A, Garcon D, et al. PCSK9 is not secreted from mature differentiated intestinal cells. J Lipid Res 2021; 62:100096. https://doi.org/10.1016/j.jlr.2021.100096
  84. Garcon D, Moreau F, Ayer A, et al. Circulating Rather Than Intestinal PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Regulates Postprandial Lipemia in Mice. Arterioscler Thromb Vasc Biol 2020; 40:2084-94. https://doi.org/10.1161/ATVBAHA.120.314194
  85. Ooi TC, Krysa JA, Chaker S, et al. The Effect of PCSK9 Loss-of-Function Variants on the Postprandial Lipid and ApoB-Lipoprotein Response. J Clin Endocrinol Metab 2017; 102:3452-60. https://doi.org/10.1210/jc.2017-00684
  86. Taskinen MR, Bjornson E, Andersson L, et al. Impact of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab on the postprandial responses of triglyceride-rich lipoproteins in type II diabetic subjects. J Clin Lipidol 2020; 14:77-87. https://doi.org/10.1016/j.jacl.2019.12.003
  87. Burggraaf B, Pouw NMC, Arroyo SF, et al. A placebo-controlled proof-of-concept study of alirocumab on postprandial lipids and vascular elasticity in insulin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab 2020; 22:807-16. https://doi.org/10.1111/dom.13960
  88. Chan DC, Watts GF, Somaratne R, et al. Comparative Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition and Statins on Postprandial Triglyceride-Rich Lipoprotein Metabolism. Arterioscler Thromb Vasc Biol 2018; 38:1644-55. https://doi.org/10.1161/ATVBAHA.118.310882
  89. Reyes-Soffer G, Pavlyha M, Ngai C, et al. Effects of PCSK9 Inhibition With Alirocumab on Lipoprotein Metabolism in Healthy Humans. Circulation 2017; 135:352-62. https://doi.org/10.1161/CIRCULATIONAHA.116.025253
  90. Rashid S, Tavori H, Brown PE, et al. Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms. Circulation 2014; 130:431-41. https://doi.org/10.1161/CIRCULATIONAHA.113.006720
  91. 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; 227:297-306. https://doi.org/10.1016/j.atherosclerosis.2013.01.023
  92. Drouin-Chartier JP, Tremblay AJ, Hogue JC, et al. Plasma PCSK9 correlates with apoB-48-containing triglyceride-rich lipoprotein production in men with insulin resistance. J Lipid Res 2018; 59:1501-9. https://doi.org/10.1194/jlr.M086264
  93. Khedoe PP, Hoeke G, Kooijman S, et al. Brown adipose tissue takes up plasma triglycerides mostly after lipolysis. J Lipid Res 2015; 56:51-9. https://doi.org/10.1194/jlr.M052746
  94. Zhang Y, McGillicuddy FC, Hinkle CC, et al. Adipocyte modulation of high-density lipoprotein cholesterol. Circulation 2010; 121:1347-55. https://doi.org/10.1161/CIRCULATIONAHA.109.897330
  95. Roubtsova A, Munkonda MN, 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; 31:785-91. https://doi.org/10.1161/ATVBAHA.110.220988
  96. 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; 35:2517-25. https://doi.org/10.1161/ATVBAHA.115.306032
  97. Bordicchia M, Spannella F, Ferretti G, et al. PCSK9 is Expressed in Human Visceral Adipose Tissue and Regulated by Insulin and Cardiac Natriuretic Peptides. Int J Mol Sci 2019; 20. https://doi.org/10.3390/ijms20020245
  98. Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004; 24:1454-9. https://doi.org/10.1161/01.ATV.0000134621.14315.43
  99. Shu X, Wu J, Zhang T, et al. Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes PCSK9-Dependent Adipose Insulin Resistance. Nutrients 2022; 14. https://doi.org/10.3390/nu14245314
  100. Cyr Y, Lamantia V, Bissonnette S, et al. Lower plasma PCSK9 in normocholesterolemic subjects is associated with upregulated adipose tissue surface-expression of LDLR and CD36 and NLRP3 inflammasome. Physiol Rep 2021; 9:e14721. https://doi.org/10.14814/phy2.14721
  101. Faraj M. LDL, LDL receptors, and PCSK9 as modulators of the risk for type 2 diabetes: a focus on white adipose tissue. J Biomed Res 2020; 34:251-9. https://doi.org/10.7555/JBR.34.20190124
  102. Iacobellis G. Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol 2015; 11:363-71. https://doi.org/10.1038/nrendo.2015.58
  103. Li C, Liu X, Adhikari BK, et al. The role of epicardial adipose tissue dysfunction in cardiovascular diseases: an overview of pathophysiology, evaluation, and management. Front Endocrinol (Lausanne) 2023; 14:1167952. https://doi.org/10.3389/fendo.2023.1167952
  104. Dozio E, Ruscica M, Vianello E, et al. PCSK9 Expression in Epicardial Adipose Tissue: Molecular Association with Local Tissue Inflammation. Mediators Inflamm 2020; 2020:1348913. https://doi.org/10.1155/2020/1348913

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