PCSK9

In February 2003, Nabil Seidah and Jae Byun, a scientist at the Clinical Research Institute of Montreal in Canada, discovered a novel human proprotein convertase, the gene for which was located on the short arm of chromosome 1.{{cite journal |vauthors=Hall SS |date=April 2013 |title=Genetics: a gene of rare effect |journal=Nature |volume=496 |issue=7444 |pages=152–155 |bibcode=2013Natur.496..152H |doi=10.1038/496152a |pmid=23579660 |doi-access=free}} Meanwhile, a lab led by Catherine Boileau at the Necker-Enfants Malades Hospital in Paris had been following families with familial hypercholesterolaemia, a genetic condition that, in 90% of cases causes coronary artery disease (FRAMINGHAM study) and in 60% of cases may lead to an early death;{{cite journal |vauthors=Sijbrands EJ, Westendorp RG, Defesche JC, de Meier PH, Smelt AH, Kastelein JJ |date=April 2001 |title=Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study |journal=The BMJ |volume=322 |issue=7293 |pages=1019–1023 |doi=10.1136/bmj.322.7293.1019 |pmc=31037 |pmid=11325764}} they had identified a mutation on chromosome 1 carried by some of these families, but had been unable to identify the relevant gene. The labs got together and by the end of the year published their work, linking mutations in the gene, now identified as PCSK9, to the condition. In their paper, they speculated that the mutations might make the gene overactive. In that same year, investigators at Rockefeller University and University of Texas Southwestern had discovered the same protein in mice, and had worked out the novel pathway that regulates LDL cholesterol in which PCSK9 is involved, and it soon became clear that the mutations identified in France led to excessive PCSK9 activity, and thus excessive removal of the LDL receptor, leaving people carrying the mutations with too much LDL cholesterol. Meanwhile, Helen H. Hobbs and Jonathan Cohen at UT-Southwestern had been studying people with very high and very low cholesterol, and had been collecting DNA samples.Parag H. Joshi, Seth S. Martin, and Roger S. Blumenthal, "[https://www.healio.com/cardiology/chd-prevention/news/print/cardiology-today/%7Bd531fcd9-ea52-4230-b412-da9270344fff%7D/the-fascinating-story-of-pcsk9-inhibition-insights-and-perspective-from-acc The fascinating story of PCSK9 inhibition: Insights and perspective from ACC]", Cardiology Today, May 2014. Retrieved 5 October 2018. With the new knowledge about the role of PCSK9 and its location in the genome, they sequenced the relevant region of chromosome 1 in people with very low cholesterol and they found nonsense mutations in the gene, thus validating PCSK9 as a biological target for drug discovery.{{cite journal |vauthors=Abifadel M, Elbitar S, El Khoury P, Ghaleb Y, Chémaly M, Moussalli ML, Rabès JP, Varret M, Boileau C |date=September 2014 |title=Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs |journal=Current Atherosclerosis Reports |volume=16 |issue=9 |pages=439 |doi=10.1007/s11883-014-0439-8 |pmid=25052769 |s2cid=207325099 |via=SpringerLink}}

In July 2015, the FDA approved the first PCSK9 Inhibitor drugs for medical use.{{cite press release |title=FDA approves Praluent to treat certain patients with high cholesterol |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm |access-date=26 July 2015 |date=24 July 2015 |archive-url=https://web.archive.org/web/20150726104705/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm |archive-date=26 July 2015 |publisher=US FDA}}

The PCSK9 gene resides on chromosome 1 at the band 1p32.3{{Cite web |date=1 January 2020 |title=PCSK9 gene |url=https://medlineplus.gov/genetics/gene/pcsk9/ |website=MedlinePlus |publisher=National Library of Medicine (US) |publication-place=Bethesda, Maryland}} and includes 15 exons.{{cite web |date=15 May 2023 |title=PCSK9 proprotein convertase subtilisin/kexin type 9 [Homo sapiens (human)] |url=https://www.ncbi.nlm.nih.gov/gene/255738 |access-date=20 May 2023 |website=Gene |publisher=NCBI |at=Genomic context}} This gene produces two isoforms through alternative splicing.{{cite web |date=3 May 2023 |title=PCSK9 - Proprotein convertase subtilisin/kexin type 9 precursor - Homo sapiens (Human) |url=https://www.uniprot.org/uniprotkb/Q8NBP7/entry#sequences |access-date=20 May 2023 |website=UniProt}}{{Rp|location=Sequence & Isoform}}

File:PDB 2p4e EBI.png

PCSK9 is a member of the peptidase S8 family.{{Rp|location=Family & Domains}}

The solved structure of PCSK9 reveals four major components in the pre-processed protein: the signal peptide (residues 1-30); the N-terminal prodomain (residues 31–152); the catalytic domain (residues 153–425); and the C-terminal domain (residues 426–692), which is further divided into three modules.{{cite journal |vauthors=Du F, Hui Y, Zhang M, Linton MF, Fazio S, Fan D |date=December 2011 |title=Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein |journal=Journal of Biological Chemistry |volume=286 |issue=50 |pages=43054–43061 |doi=10.1074/jbc.M111.273474 |pmc=3234880 |pmid=22027821 |doi-access=free}} The N-terminal prodomain has a flexible crystal structure and is responsible for regulating PCSK9 function by interacting with and blocking the catalytic domain, which otherwise binds the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR.{{cite journal |vauthors=Lo Surdo P, Bottomley MJ, Calzetta A, Settembre EC, Cirillo A, Pandit S, Ni YG, Hubbard B, Sitlani A, Carfí A |date=December 2011 |title=Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH |journal=EMBO Reports |volume=12 |issue=12 |pages=1300–1305 |doi=10.1038/embor.2011.205 |pmc=3245695 |pmid=22081141}}{{cite journal |vauthors=Piper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, Thibault ST, Shan B, Walker NP |date=May 2007 |title=The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol |journal=Structure |volume=15 |issue=5 |pages=545–552 |doi=10.1016/j.str.2007.04.004 |pmid=17502100 |doi-access=free}} While previous studies indicated that the C-terminal domain was uninvolved in binding LDLR,{{cite journal |vauthors=Bottomley MJ, Cirillo A, Orsatti L, Ruggeri L, Fisher TS, Santoro JC, Cummings RT, Cubbon RM, Lo Surdo P, Calzetta A, Noto A, Baysarowich J, Mattu M, Talamo F, De Francesco R, Sparrow CP, Sitlani A, Carfí A |date=January 2009 |title=Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants |journal=Journal of Biological Chemistry |volume=284 |issue=2 |pages=1313–1323 |doi=10.1074/jbc.M808363200 |pmid=19001363 |s2cid=25776087 |doi-access=free|hdl=2434/634756 |hdl-access=free }}{{cite journal |vauthors=Kwon HJ, Lagace TA, McNutt MC, Horton JD, Deisenhofer J |date=February 2008 |title=Molecular basis for LDL receptor recognition by PCSK9 |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=105 |issue=6 |pages=1820–1825 |bibcode=2008PNAS..105.1820K |doi=10.1073/pnas.0712064105 |pmc=2538846 |pmid=18250299 |doi-access=free}} a recent study by Du et al. demonstrated that the C-terminal domain does bind LDLR. The secretion of PCSK9 is largely dependent on the autocleavage of the signal peptide and N-terminal prodomain, though the N-terminal prodomain retains its association with the catalytic domain. In particular, residues 61–70 in the N-terminal prodomain are crucial for its autoprocessing.

PCSK9 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. It is expressed mainly in liver, intestine, kidney, skin and the central nervous system.{{cite journal | vauthors = Norata GD, Tibolla G, Catapano AL | title = Targeting PCSK9 for hypercholesterolemia | journal = Annual Review of Pharmacology and Toxicology | volume = 54 | pages = 273–293 | date = 2014-01-01 | pmid = 24160703 | doi = 10.1146/annurev-pharmtox-011613-140025 | doi-access = free }} After being processed in the ER, PCSK9 co-localizes with the protein sortilin on its way through the Golgi and trans-Golgi complex. A PCSK9-sortilin interaction is proposed to be required for cellular secretion of PCSK9.{{cite journal | vauthors = Gustafsen C, Kjolby M, Nyegaard M, Mattheisen M, Lundhede J, Buttenschøn H, Mors O, Bentzon JF, Madsen P, Nykjaer A, Glerup S | title = The hypercholesterolemia-risk gene SORT1 facilitates PCSK9 secretion | journal = Cell Metabolism | volume = 19 | issue = 2 | pages = 310–318 | date = February 2014 | pmid = 24506872 | doi = 10.1016/j.cmet.2013.12.006 | doi-access = free }} In healthy humans, plasma PCSK9 levels directly correlate with plasma sortilin levels, following a diurnal rhythm similar to cholesterol synthesis.{{cite journal | vauthors = Schulz R, Schlüter KD, Laufs U | title = Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9) | journal = Basic Research in Cardiology | volume = 110 | issue = 2 | pages = 4 | date = March 2015 | pmid = 25600226 | pmc = 4298671 | doi = 10.1007/s00395-015-0463-z }}{{cite journal | vauthors = Cariou B, Langhi C, Le Bras M, Bortolotti M, Lê KA, Theytaz F, Le May C, Guyomarc'h-Delasalle B, Zaïr Y, Kreis R, Boesch C, Krempf M, Tappy L, Costet P | title = Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets | journal = Nutrition & Metabolism | volume = 10 | issue = 1 | pages = 4 | date = January 2013 | pmid = 23298392 | pmc = 3548771 | doi = 10.1186/1743-7075-10-4 | doi-access = free }} The plasma PCSK9 concentration is higher in women compared to men, and the PCSK9 concentrations decrease with age in men but increase in women, suggesting that estrogen level most likely plays a role.{{cite journal | vauthors = Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH | title = Genetic and metabolic determinants of plasma PCSK9 levels | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 94 | issue = 7 | pages = 2537–2543 | date = July 2009 | pmid = 19351729 | pmc = 2708952 | doi = 10.1210/jc.2009-0141 }}{{cite journal | vauthors = Baass A, Dubuc G, Tremblay M, Delvin EE, O'Loughlin J, Levy E, Davignon J, Lambert M | title = Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents | journal = Clinical Chemistry | volume = 55 | issue = 9 | pages = 1637–1645 | date = September 2009 | pmid = 19628659 | doi = 10.1373/clinchem.2009.126987 | doi-access = free }} PCSK9 gene expression can be regulated by sterol-response element binding proteins (SREBP-1/2), which also controls LDLR expression.

As a negative post-translational regulator of the low-density lipoprotein receptor (LDLR), PCSK9 plays a major role in cholesterol homeostasis. Upon binding of low-density lipoprotein (LDL) cholesterol to the LDL receptor, the resulting LDLR-LDL complex is internalized. When exposed to the acidic environment within the resulting endosome LDLR adopts a hairpin conformation.{{cite journal | vauthors = Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD, Cohen JC, Hobbs HH | title = 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 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 25 | pages = 18602–18612 | date = June 2007 | pmid = 17452316 | doi = 10.1074/jbc.M702027200 | doi-access = free }} This conformational change in turn induces the dissociation of the LDL-LDLR complex, allowing LDLR to be recycled back to the plasma membrane. Binding of PCSK9 to cell surface LDLR (through the LDLR EGF-A domain) also induces LDLR internalization. However, unlike LDL binding, PCSK9 prevents LDLR from undergoing a conformational change. This inhibition redirects LDLR to a lysosome where it is degraded. Thus, PCSK9 lowers cell surface expression of LDLR and thereby decreases metabolism of LDL-particles, which in turn may lead to hypercholesterolemia. PCSK9 also plays an important role in triglyceride-rich apoB lipoprotein production in small intestine and postprandial lipemia.{{cite journal | vauthors = Bergeron N, Phan BA, Ding Y, Fong A, Krauss RM | title = Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk | journal = Circulation | volume = 132 | issue = 17 | pages = 1648–1666 | date = October 2015 | pmid = 26503748 | doi = 10.1161/CIRCULATIONAHA.115.016080 | doi-access = free }}{{cite journal | vauthors = Le May C, Kourimate S, Langhi C, Chétiveaux M, Jarry A, Comera C, Collet X, Kuipers F, Krempf M, Cariou B, Costet P | title = Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 29 | issue = 5 | pages = 684–690 | date = May 2009 | pmid = 19265033 | doi = 10.1161/ATVBAHA.108.181586 | doi-access = free }}{{cite journal | vauthors = Rashid S, Tavori H, Brown PE, Linton MF, He J, Giunzioni I, Fazio S | title = 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 | journal = Circulation | volume = 130 | issue = 5 | pages = 431–441 | date = July 2014 | pmid = 25070550 | pmc = 4115295 | doi = 10.1161/CIRCULATIONAHA.113.006720 }}

ApoB lipoprotein, PCSK9, and the genes involved in cholesterol synthesis are highly expressed in the epidermis.{{cite journal | vauthors = Merleev A, Ji-Xu A, Toussi A, Tsoi LC, Le ST, Luxardi G, Xing X, Wasikowski R, Liakos W, Brüggen MC, Elder JT, Adamopoulos IE, Izumiya Y, Leal AR, Li Q, Kuzminykh NY, Kirane A, Marusina AI, Gudjonsson JE, Maverakis E | title = Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G | journal = JCI Insight | volume = 7 | issue = 16 | pages = e141193 | date = August 2022 | pmid = 35862195 | pmc = 9462487 | doi = 10.1172/jci.insight.141193 }}{{cite journal | vauthors = Merleev AA, Le ST, Alexanian C, Toussi A, Xie Y, Marusina AI, Watkins SM, Patel F, Billi AC, Wiedemann J, Izumiya Y, Kumar A, Uppala R, Kahlenberg JM, Liu FT, Adamopoulos IE, Wang EA, Ma C, Cheng MY, Xiong H, Kirane A, Luxardi G, Andersen B, Tsoi LC, Lebrilla CB, Gudjonsson JE, Maverakis E | title = Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes | journal = JCI Insight | volume = 7 | issue = 16 | pages = e159762 | date = August 2022 | pmid = 35900871 | pmc = 9462509 | doi = 10.1172/jci.insight.159762 }} The cutaneous expression of PCSK9 is likely important for proper skin barrier formation as ceramides, free fatty acids, and cholesterol are the three major components of the epidermal lipid barrier.{{cite journal | vauthors = Elias PM | title = Epidermal lipids, barrier function, and desquamation | journal = The Journal of Investigative Dermatology | volume = 80 | issue = Suppl | pages = 44s–49s | date = June 1983 | doi = 10.1038/jid.1983.12 | pmid = 6189923 | doi-access = free }} Matching its function in cholesterol homeostasis, there is a gradient of PCSK9 expression in the epidermis. PCSK9 is selectively expressed in basal and spinous layer keratinocytes with little to no expression in granular layer keratinocytes. In contrast to basal layer keratinocytes, granular layer keratinocytes release large amounts of cholesterol and other lipids to form a lipid rich "mortar" in the intracellular space between keratinocytes. In addition to its likely role in epidermal lipid barrier formation, PCSK9 has also been linked to skin inflammation. For example, genetic variants of PCSK9 have been linked psoriasis, and knockdown expression of PCSK9 in keratinocytes results in increase expression of IL-36G and other keratinocyte-derived inflammatory mediators.

PCSK9 may also have a role in the differentiation of cortical neurons.

Variants of PCSK9 can reduce or increase circulating cholesterol. LDL-particles are removed from the blood when they bind to LDLR on the surface of cells, including liver cells, and are taken inside the cells. When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. PCSK9 degrades LDLR by preventing the hairpin conformational change of LDLR.{{cite journal | vauthors = Zhang DW, Garuti R, Tang WJ, Cohen JC, Hobbs HH | title = Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 35 | pages = 13045–13050 | date = September 2008 | pmid = 18753623 | pmc = 2526098 | doi = 10.1073/pnas.0806312105 | doi-access = free | bibcode = 2008PNAS..10513045Z }} If PCSK9 does not bind, the receptor will return to the surface of the cell and can continue to remove LDL-particles from the bloodstream.

Other variants are associated with a rare autosomal dominant familial hypercholesterolemia (HCHOLA3). The mutations increase its protease activity, reducing LDLR levels and preventing the uptake of cholesterol into the cells.

In humans, PCSK9 was initially discovered as a protein expressed in the brain.{{cite journal | vauthors = O'Connell EM, Lohoff FW | title = Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in the Brain and Relevance for Neuropsychiatric Disorders | journal = Frontiers in Neuroscience | volume = 14 | issue = | pages = 609 | date = 2020 | pmid = 32595449 | pmc = 7303295 | doi = 10.3389/fnins.2020.00609 | doi-access = free }}{{cite journal | vauthors = Norata GD, Tavori H, Pirillo A, Fazio S, Catapano AL | title = Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering | journal = Cardiovascular Research | volume = 112 | issue = 1 | pages = 429–442 | date = October 2016 | pmid = 27496869 | pmc = 5031950 | doi = 10.1093/cvr/cvw194 }} However, it has also been described in the kidney, the pancreas, liver and small intestine. Recent evidence indicate that PCSK9 is highly expressed in arterial walls such as endothelium, smooth muscle cells, and macrophages, with a local effect that can regulate vascular homeostasis and atherosclerosis.{{cite journal | vauthors = Ferri N, Tibolla G, Pirillo A, Cipollone F, Mezzetti A, Pacia S, Corsini A, Catapano AL | title = Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels | journal = Atherosclerosis | volume = 220 | issue = 2 | pages = 381–386 | date = February 2012 | pmid = 22176652 | doi = 10.1016/j.atherosclerosis.2011.11.026 }}{{cite journal | vauthors = Wu CY, Tang ZH, Jiang L, Li XF, Jiang ZS, Liu LS | title = PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3 pathway | journal = Molecular and Cellular Biochemistry | volume = 359 | issue = 1–2 | pages = 347–358 | date = January 2012 | pmid = 21847580 | doi = 10.1007/s11010-011-1028-6 | s2cid = 8017156 }}{{cite journal | vauthors = Giunzioni I, Tavori H, Covarrubias R, Major AS, Ding L, Zhang Y, DeVay RM, Hong L, Fan D, Predazzi IM, Rashid S, Linton MF, Fazio S | title = Local effects of human PCSK9 on the atherosclerotic lesion | journal = The Journal of Pathology | volume = 238 | issue = 1 | pages = 52–62 | date = January 2016 | pmid = 26333678 | pmc = 5346023 | doi = 10.1002/path.4630 }} Accordingly, it is now very clear that PCSK9 has pro-atherosclerotic effects and regulates lipoprotein synthesis.{{cite journal | vauthors = Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH | title = Sequence variations in PCSK9, low LDL, and protection against coronary heart disease | journal = The New England Journal of Medicine | volume = 354 | issue = 12 | pages = 1264–1272 | date = March 2006 | pmid = 16554528 | doi = 10.1056/NEJMoa054013 | doi-access = free }}

As PCSK9 binds to LDLR, which prevents the removal of LDL-particles from the blood plasma, several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia).{{cite journal | vauthors = Groves C, Shetty C, Strange RC, Waldron J, Ramachandran S | title = A study in high-risk, maximally pretreated patients to determine the potential use of PCSK9 inhibitors at various thresholds of total and LDL cholesterol levels | journal = Postgraduate Medical Journal | volume = 93 | issue = 1098 | pages = 205–208 | date = April 2017 | pmid = 27531965 | doi = 10.1136/postgradmedj-2016-134062 | s2cid = 22438076 | url = http://eprints.keele.ac.uk/2147/1/R%20Strange%20-%20A%20study%20in%20high%20risk%2C%20maximally%20pre-treated%20patients%20to%20determine%20the%20potential%20use%20of....pdf }}{{cite journal | vauthors = Robinson JG | title = Nonstatins and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Role in Non-Familial Hypercholesterolemia | journal = Progress in Cardiovascular Diseases | volume = 59 | issue = 2 | pages = 165–171 | date = August 2016 | pmid = 27498088 | doi = 10.1016/j.pcad.2016.07.011 }}{{cite journal | vauthors = Rosenson RS, Jacobson TA, Preiss D, Djedjos SC, Dent R, Bridges I, Miller M | title = Erratum to: Efficacy and Safety of the PCSK9 Inhibitor Evolocumab in Patients with Mixed Hyperlipidemia | journal = Cardiovascular Drugs and Therapy | volume = 30 | issue = 5 | pages = 537 | date = October 2016 | pmid = 27497929 | pmc = 6828239 | doi = 10.1007/s10557-016-6684-z }}{{cite journal | vauthors = Peng W, Qiang F, Peng W, Qian Z, Ke Z, Yi L, Jian Z, Chongrong Q | title = Therapeutic efficacy of PCSK9 monoclonal antibodies in statin-nonresponsive patients with hypercholesterolemia and dyslipidemia: A systematic review and meta-analysis | journal = International Journal of Cardiology | volume = 222 | pages = 119–129 | date = November 2016 | pmid = 27494723 | doi = 10.1016/j.ijcard.2016.07.239 }}{{cite journal | vauthors = Urban D, Pöss J, Böhm M, Laufs U | title = Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis | journal = Journal of the American College of Cardiology | volume = 62 | issue = 16 | pages = 1401–1408 | date = October 2013 | pmid = 23973703 | doi = 10.1016/j.jacc.2013.07.056 | doi-access = free }}{{cite journal | vauthors = Norata GD, Tibolla G, Catapano AL | title = PCSK9 inhibition for the treatment of hypercholesterolemia: promises and emerging challenges | journal = Vascular Pharmacology | volume = 62 | issue = 2 | pages = 103–111 | date = August 2014 | pmid = 24924410 | doi = 10.1016/j.vph.2014.05.011 }} Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.{{cite journal | vauthors = Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH | title = Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9 | journal = Nature Genetics | volume = 37 | issue = 2 | pages = 161–165 | date = February 2005 | pmid = 15654334 | doi = 10.1038/ng1509 | s2cid = 35526497 }}{{cite journal | vauthors = Kathiresan S | title = A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction | journal = The New England Journal of Medicine | volume = 358 | issue = 21 | pages = 2299–2300 | date = May 2008 | pmid = 18499582 | doi = 10.1056/NEJMc0707445 | doi-access = free }}

In addition to its lipoprotein synthetic and pro-atherosclerotic effects, PCSK9 is involved in glucose metabolism and obesity,{{cite journal | vauthors = Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ | title = Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial | journal = Lancet | volume = 380 | issue = 9841 | pages = 565–571 | date = August 2012 | pmid = 22883507 | pmc = 3774022 | doi = 10.1016/S0140-6736(12)61190-8 }} regulation of re-absorption of sodium in the kidney which is relevant in hypertension.{{cite journal | vauthors = Berger JM, Vaillant N, Le May C, Calderon C, Brégeon J, Prieur X, Hadchouel J, Loirand G, Cariou B | title = PCSK9-deficiency does not alter blood pressure and sodium balance in mouse models of hypertension | journal = Atherosclerosis | volume = 239 | issue = 1 | pages = 252–259 | date = March 2015 | pmid = 25621930 | doi = 10.1016/j.atherosclerosis.2015.01.012 }}{{cite journal | vauthors = Sharotri V, Collier DM, Olson DR, Zhou R, Snyder PM | title = Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9) | journal = The Journal of Biological Chemistry | volume = 287 | issue = 23 | pages = 19266–19274 | date = June 2012 | pmid = 22493497 | pmc = 3365958 | doi = 10.1074/jbc.M112.363382 | doi-access = free }} Furthermore, PCSK9 may be involved in bacterial or viral infections and sepsis.{{cite journal | vauthors = Magnasco L, Sepulcri C, Antonello RM, Di Bella S, Labate L, Luzzati R, Giacobbe DR, Bassetti M | title = The Role of PCSK9 in Infectious Diseases | journal = Current Medicinal Chemistry | volume = 29 | issue = 6 | pages = 1000–1015 | date = 2022 | pmid = 34269657 | doi = 10.2174/0929867328666210714160343 | hdl = 11368/2998545 | s2cid = 235959945 | hdl-access = free }}{{cite journal | vauthors = Norata GD, Pirillo A, Ammirati E, Catapano AL | title = Emerging role of high density lipoproteins as a player in the immune system | journal = Atherosclerosis | volume = 220 | issue = 1 | pages = 11–21 | date = January 2012 | pmid = 21783193 | doi = 10.1016/j.atherosclerosis.2011.06.045 }}{{cite journal | vauthors = Diedrich G | title = How does hepatitis C virus enter cells? | journal = The FEBS Journal | volume = 273 | issue = 17 | pages = 3871–3885 | date = September 2006 | pmid = 16934030 | doi = 10.1111/j.1742-4658.2006.05379.x | s2cid = 28432320 | doi-access = free }} In the brain the role of PCSK9 is still controversial and may be either pro-apoptotic or protective in the development of the nervous system. PCSK9 levels have been detected in the cerebrospinal fluid at a 50-60 times lower level than in serum.{{cite journal | vauthors = Chen YQ, Troutt JS, Konrad RJ | title = PCSK9 is present in human cerebrospinal fluid and is maintained at remarkably constant concentrations throughout the course of the day | journal = Lipids | volume = 49 | issue = 5 | pages = 445–455 | date = May 2014 | pmid = 24659111 | doi = 10.1007/s11745-014-3895-6 | s2cid = 4052058 }}

A multi-locus genetic risk score study based on a combination of 27 loci including the PCSK9 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).

{{Multiple image

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| image1 = PCSK9-mediated degradation of LDLR.jpg

| caption1 = Under normal conditions, PCSK9 binds to the LDL-LDLR-complex and directs both to the lysosome for degradation.

| image2 = PCSK9_inhibition.jpg

| caption2 = PCSK9-inhibitors that prevent the association between PCSK9 and the LDLR mean that when LDLR is internalised, it releases the LDL before reaching the lysosome and is instead recycled to the cell surface to be available for binding again.

| total_width = 400

}}

Several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia). Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.

The PCSK9 inhibitor drugs Evolocumab and Alirocumab are now approved by the FDA to treat familial hypercholesterolemia.

=== As a drug target ===

Drugs can inhibit PCSK9, leading to lowered circulating LDL particle concentrations. Since LDL particle concentrations are thought by many experts to be a driver of cardiovascular disease like heart attacks, it is plausible that these drugs may also reduce the risk of such diseases. Clinical studies, including phase III clinical trials, are now underway to describe the effect of PCSK9 inhibition on cardiovascular disease, and the safety and efficacy profile of the drugs. Among those inhibitors under development in December 2013 were the antibodies alirocumab, evolocumab, 1D05-IgG2 (Merck), RG-7652 and LY3015014, as well as the RNAi therapeutic inclisiran.{{cite journal | vauthors = Sheridan C | title = Phase 3 data for PCSK9 inhibitor wows | journal = Nature Biotechnology | volume = 31 | issue = 12 | pages = 1057–1058 | date = December 2013 | pmid = 24316621 | doi = 10.1038/nbt1213-1057 | s2cid = 34214247 }} PCSK9 inhibitors are promising therapeutics for the treatment of people who exhibit statin intolerance, or as a way to bypass frequent dosage of statins for higher LDL concentration reduction.{{cite journal | vauthors = Stein EA, Raal FJ | title = New therapies for reducing low-density lipoprotein cholesterol | journal = Endocrinology and Metabolism Clinics of North America | volume = 43 | issue = 4 | pages = 1007–1033 | date = December 2014 | pmid = 25432394 | doi = 10.1016/j.ecl.2014.08.008 }}{{cite journal | vauthors = Vogel RA | title = PCSK9 inhibition: the next statin? | journal = Journal of the American College of Cardiology | volume = 59 | issue = 25 | pages = 2354–2355 | date = June 2012 | pmid = 22465426 | doi = 10.1016/j.jacc.2012.03.011 | doi-access = free }}

A review published in 2015 concluded that these agents, when used in patients with high LDL-particle concentrations (thus at greatly elevated risk for cardiovascular disease) seem to be safe and effective at reducing all-cause mortality, cardiovascular mortality, and heart attacks.{{cite journal | vauthors = Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, Brockmeyer M, Kandzari DE, Kubica JM, D'Agostino RB, Kubica J, Volpe M, Agewall S, Kereiakes DJ, Kelm M | title = Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis | journal = Annals of Internal Medicine | volume = 163 | issue = 1 | pages = 40–51 | date = July 2015 | pmid = 25915661 | doi = 10.7326/M14-2957 | s2cid = 207538324 }} However a 2020 review concluded that while PCSK9 inhibitor treatment provides additional benefits beyond maximally tolerated statin therapy in high-risk individuals,{{cite journal | vauthors = Durairaj A, Sabates A, Nieves J, Moraes B, Baum S | title = Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Its Inhibitors: a Review of Physiology, Biology, and Clinical Data | journal = Current Treatment Options in Cardiovascular Medicine | volume = 19 | issue = 8 | pages = 58 | date = August 2017 | pmid = 28639183 | doi = 10.1007/s11936-017-0556-0 | s2cid = 25301414 }} PCSK9 inhibitor use probably produces little or no difference in mortality.{{cite journal | vauthors = Schmidt AF, Carter JL, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, Casas JP | title = PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 12 | pages = CD011748 | date = October 2020 | pmid = 33078867 | pmc = 8094613 | doi = 10.1002/14651858.CD011748.pub3 }}

Regeneron Pharmaceuticals (in collaboration with Sanofi) became the first to market a PCSK9 inhibitor, with a competitor Amgen reaching market slightly later. Prices were very high, inhibiting adoption. The drugs are approved by the FDA for treatment of hypercholesterolemia, notably the genetic condition heterozygous familial hypercholesterolemia which causes high cholesterol levels and heart attacks at a young age. These drugs were later approved by the FDA for the reduction of cardiovascular events including a reduction in all-cause mortality.{{cite news| vauthors = Wendling P | title=FDA Expands Indication for PCSK9 Alirocumab (Praluent) | website=Medscape | date=30 April 2019 | url=https://www.medscape.com/viewarticle/912382}}

In recent meta-analyses, early initiation of PCSK9 inhibitors within 48 to 72 hours following acute coronary syndrome (ACS) in addition to high dose statin therapy was associated with rapid reduction in LDL-C level, and potentially other lipid profiles such as triglycerides and total cholesterol level at 4 to 12 weeks after the cardiac event. This translates into a significant reduction in ACS-related hospital readmission and the need for coronary revascularization in short-term follow-up at 1 to 18 months.{{cite journal | vauthors = Nagendra L, Mahajan K, Gupta G, Dutta D | title = Impact of early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors in patients with acute coronary syndrome: A systematic review meta-analysis | journal = Indian Heart Journal | volume = 75 | issue = 6 | pages = 416–422 | date = Sep 2023 | pmid = 37777180 | pmc = 10774595 | doi = 10.1016/j.ihj.2023.09.005 | doi-access = free }}{{Cite journal | vauthors = Hosseini K, Soleimani H, Maleki S, Nasrollahizadeh A, Tayebi S, Nelson J, Heffron SP | title = Early administration of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with acute coronary syndrome: a systematic review and meta-analysis | journal = BMC Cardiovascular Disorders | volume = 24 | issue = 1 | pages = 395 | date = 2024-07-30 | pmid = 39080549 | pmc = 11287928 | doi = 10.1186/s12872-024-04057-w | language = en | doi-access = free | issn = 1471-2261 }}{{Cite journal | vauthors = Yifan D, Yue M, Yubin Z, Jiapei G, Xun S, Shenghu H, Li Z, Jing Z | title = The impact of early in-hospital use of PCSK9 inhibitors on cardiovascular outcomes in acute coronary syndrome patients: A systematic review and meta-analysis | journal = International Journal of Cardiology | volume = 399 | pages = 131775 | date = March 2024 | pmid = 38211676 | doi = 10.1016/j.ijcard.2024.131775 | url = https://linkinghub.elsevier.com/retrieve/pii/S0167527324001050 | language = en | url-access = subscription }}

An FDA warning in March 2014 about possible cognitive adverse effects of PCSK9 inhibition caused concern, as the FDA asked companies to include neurocognitive testing into their Phase III clinical trials.{{cite news | vauthors = Carroll J | work = FierceBiotech | date = 7 March 2014 | url = http://www.fiercebiotech.com/story/regeneron-sanofi-and-amgen-shares-suffer-fdas-frets-about-pcsk9-drug/2014-03-07 | title = Regeneron, Sanofi and Amgen shares suffer on FDA's frets about PCSK9 class }}

{{update section|date=January 2025}}

A number of monoclonal antibodies that bind to and inhibit PCSK9 near the catalytic domain were in clinical trials {{as of|2014|lc=y}}. These include evolocumab (Amgen), bococizumab (Pfizer), and alirocumab (Sanofi/Regeneron Pharmaceuticals). {{as of|2015|7}}, the EU approved these drugs including Evolocumab/Amgen according to Medscape news agency report. PCSK9 inhibitors have been shown to significantly reduce LDL-C levels and increase HDL-C levels significantly.{{cite journal | vauthors = Imran T | title = Proprotein convertase subtilisn/kexin type 9 inhibitors and small interfering RNA therapy for cardiovascular risk reduction: A systematic review and meta-analysis. | journal = Plos One | volume = 18 | issue = 12 | pages = e0295359 | date = 2023 | pmid = 38055686 | pmc = 10699593 | doi = 10.1371/journal.pone.0295359 | doi-access = free | bibcode = 2023PLoSO..1895359I }}{{cite journal | vauthors = Khan S | title = PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis | journal = BMJ | location = Clinical Research Ed. | volume = 377 | pages = e069116 | date = 2022 | pmid = 35508321 | doi = 10.1136/bmj-2021-069116 }} They were found to lower the incidence of myocardial infarction and stroke in individuals at high cardiovascular risk (over 15% using PREDICT cardiovascular disease calculator), such as those with at least five risk factors, established cardiovascular disease, or hereditary lipid disorders without cardiovascular risk factor, but not in those at low to moderate risk. A 2023 meta-analysis has indicated that alirocumab may reduce all-cause mortality, whereas evolocumab has no significant effect on all-cause mortality. The efficacy of bococizumab remains unclear, as its development was discontinued by Pfizer in 2016.{{cite web | vauthors = Pfizer | title = Pfizer Discontinues Global Development of Bococizumab, Its Investigational PCSK9 Inhibitor. | url = https://www.pfizer.com/news/press-release/press-release-detail/pfizer_discontinues_global_development_of_bococizumab_its_investigational_pcsk9_inhibitor | access-date = 4 May 2025 }} The most recent guidelines for cholesterol management from the American Heart Association and American College of Cardiology now provide guidance for when PCSK9 inhibitors should be considered, particularly focusing on cases in which maximally tolerated statin and ezetimibe fail to achieve goal LDL reduction.{{cite journal | vauthors = Alenghat FJ, Davis AM | title = Management of Blood Cholesterol | journal = JAMA | volume = 321 | issue = 8 | pages = 800–801 | date = February 2019 | pmid = 30715135 | pmc = 6679800 | doi = 10.1001/jama.2019.0015 }}

A possible side effect of the monoclonal antibody might be irritation at the injection site. Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.{{cite journal | vauthors = 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 | title = 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 | journal = Lancet | volume = 383 | issue = 9911 | pages = 60–68 | date = January 2014 | pmid = 24094767 | pmc = 4387547 | doi = 10.1016/S0140-6736(13)61914-5 }}

Peptides that mimics the EGFA domain of the LDLR were explored as potential PCSK9 inhibitors in preclinical studies but have not advanced to clinical use as of May 2025, with current treatments focusing on monoclonal antibodies, inclisiran, and conventional therapies such as statins and ezetimibe.{{Cite web | title = Search {{!}} FDA|url=https://www.fda.gov/search?s=ldl+or+cholesterol+or+hyperlipidemia+or+hdl&sort_bef_combine=rel_DESC|access-date=2025-05-06|website=www.fda.gov}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}

{{Cite journal | vauthors = Rikhi R, Shapiro MD | title = Newer and Emerging LDL-C Lowering Agents and Implications for ASCVD Residual Risk | journal = Journal of Clinical Medicine | volume = 11 | issue = 15 | pages = 4611 | date = 2022-08-08 | pmid = 35956226 | pmc = 9369522 | doi = 10.3390/jcm11154611 | doi-access = free | issn = 2077-0383 }}

The PCSK9 antisense oligonucleotide increases expression of the LDLR and decreases circulating total cholesterol levels in mice. A locked nucleic acid reduced PCSK9 mRNA levels in mice. Initial clinical trials showed positive results of ALN-PCS, which acts by means of RNA interference.

In 2021, scientists demonstrated that CRISPR gene editing can decrease blood levels of LDL cholesterol in vivo in Macaca fascicularis monkeys for months by 60% via knockdown of PCSK9 in the liver.{{cite news |title=Scientists Gene-Hacked Monkeys to Fix Their Cholesterol |url=https://futurism.com/neoscope/gene-hacked-monkeys-fix-cholesterol |access-date=13 June 2021 |work=Futurism}}{{cite journal | vauthors = Musunuru K, Chadwick AC, Mizoguchi T, Garcia SP, DeNizio JE, Reiss CW, Wang K, Iyer S, Dutta C, Clendaniel V, Amaonye M, Beach A, Berth K, Biswas S, Braun MC, Chen HM, Colace TV, Ganey JD, Gangopadhyay SA, Garrity R, Kasiewicz LN, Lavoie J, Madsen JA, Matsumoto Y, Mazzola AM, Nasrullah YS, Nneji J, Ren H, Sanjeev A, Shay M, Stahley MR, Fan SH, Tam YK, Gaudelli NM, Ciaramella G, Stolz LE, Malyala P, Cheng CJ, Rajeev KG, Rohde E, Bellinger AM, Kathiresan S | title = In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates | journal = Nature | volume = 593 | issue = 7859 | pages = 429–434 | date = May 2021 | pmid = 34012082 | doi = 10.1038/s41586-021-03534-y | s2cid = 234790939 | bibcode = 2021Natur.593..429M }}

In 2023, a clinical trial demonstrated that VERVE-101 gene therapy, which works via CRISPR gene editing, could reduce LDL cholesterol by as much as 55% in human volunteers with heterozygous familial hypercholesterolemia.{{cite web |title=CRISPR gene editing shown to permanently lower high cholesterol |url=https://arstechnica.com/health/2023/11/crispr-gene-editing-shown-to-permanently-lower-high-cholesterol/ |access-date=15 November 2023 |work=Ars Technica |date=15 November 2023 }}{{cite journal |title=VERVE-101: CRISPR-Based Gene Editing Therapy Shows Promise in Reducing LDL-C and PCSK9 Levels in Patients With HeFH |journal=American College of Cardiology |url=https://www.acc.org/Latest-in-Cardiology/Articles/2023/11/08/20/14/sun-445pm-heart1-aha-2023}}

A vaccine that targets PCSK9 has been developed to treat high LDL-particle concentrations. The vaccine uses a VLP (virus-like particle) as an immunogenic carrier of an antigenic PCSK9 peptide. VLPs consist of the outer shell of a virus particle but lack a viral genome and are unable to replicate; they can induce immune responses without causing infection. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high-titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides.{{cite journal | vauthors = Crossey E, Amar MJ, Sampson M, Peabody J, Schiller JT, Chackerian B, Remaley AT | title = A cholesterol-lowering VLP vaccine that targets PCSK9 | journal = Vaccine | volume = 33 | issue = 43 | pages = 5747–5755 | date = October 2015 | pmid = 26413878 | pmc = 4609631 | doi = 10.1016/j.vaccine.2015.09.044 }}

The plant alkaloid berberine inhibits the transcription of the PCSK9 gene in immortalized human hepatocytes in vitro, and lowers serum PCSK9 in mice and hamsters in vivo.{{cite journal | vauthors = Dong B, Li H, Singh AB, Cao A, Liu J | title = Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1α protein expression through the ubiquitin-proteasome degradation pathway | journal = The Journal of Biological Chemistry | volume = 290 | issue = 7 | pages = 4047–4058 | date = February 2015 | pmid = 25540198 | pmc = 4326815 | doi = 10.1074/jbc.M114.597229 | doi-access = free }} It has been speculated that this action contributes to the ability of berberine to lower serum cholesterol.{{cite journal | vauthors = Dong H, Zhao Y, Zhao L, Lu F | title = The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials | journal = Planta Medica | volume = 79 | issue = 6 | pages = 437–446 | date = April 2013 | pmid = 23512497 | doi = 10.1055/s-0032-1328321 | doi-access = free | bibcode = 2013PlMed..79..437D }} Annexin A2, an endogenous protein, is a natural inhibitor of PCSK9 activity.

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{{refend}}

• {{PDBe-KB2|Q8NBP7|Proprotein convertase subtilisin/kexin type 9}}