PCSK9 - Knowledge (XXG)

1704:, PCSK9, and the genes involved in cholesterol synthesis are highly expressed in the epidermis. 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. 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. 391: 368: 1637:-like repeat A (EGF-A) domain of the LDLR. While previous studies indicated that the C-terminal domain was uninvolved in binding LDLR, 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. 1804: 265: 290: 1685:

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

1515:(FRAMINGHAM study) and in 60% of cases may lead to an early death; 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 397: 296: 38: 1818: 1589: 1724:, 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. 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. 2061:) 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 1992:

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

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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

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from the blood plasma, 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

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UT-Southwestern had been studying people with very high and very low cholesterol, and had been collecting DNA samples. 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

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and other drugs were not sufficiently effective or poorly tolerated. The cost of these new medications, as of 2015, was $ 14,000 per year at full retail; judged of unclear cost effectiveness by some. While these medications are prescribed by many physicians, the payment for prescriptions are often

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for destruction. If PCSK9 is blocked, the LDL-LDLR complex separates during trafficking, with the LDL digested in the lysosome, but the LDLRs instead recycled back to the cell surface and so able to remove additional LDL-particles from the extracellular fluid. Therefore, blocking PCSK9 can lower

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In a meta-analysis involving data from 3 randomized controlled trials, early initiation of PCSK9 inhibitors within 72 hours of acute coronary event along with high dose statin was associated with a more rapid decline in cholesterol levels 4 weeks after the cardiac event, which translated into a

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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. This conformational change in turn induces the

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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

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similar to cholesterol synthesis. 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. PCSK9 gene expression can be regulated by

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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

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Abifadel M, Elbitar S, El Khoury P, Ghaleb Y, Chémaly M, Moussalli ML, et al. (September 2014). "Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs".

1633:(residues 426–692), which is further divided into three modules. 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 1773:, regulation of re-absorption of sodium in the kidney which is relevant in hypertension. Furthermore, PCSK9 may be involved in bacterial or viral infections and sepsis. In the brain the role of PCSK9 is still controversial and may be either pro- 4645:

Peng W, Qiang F, Peng W, Qian Z, Ke Z, Yi L, et al. (November 2016). "Therapeutic efficacy of PCSK9 monoclonal antibodies in statin-nonresponsive patients with hypercholesterolemia and dyslipidemia: A systematic review and meta-analysis".

1890:. However a 2020 review concluded that while PCSK9 inhibitor treatment provides additional benefits beyond maximally tolerated statin therapy in high-risk individuals, PCSK9 inhibitor use probably produces little or no difference in mortality. 5822:"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" 1662:

on its way through the Golgi and trans-Golgi complex. A PCSK9-sortilin interaction is proposed to be required for cellular secretion of PCSK9. In healthy humans, plasma PCSK9 levels directly correlate with plasma sortilin levels, following a

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Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, et al. (July 2015). "Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis".

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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

2978: 1415:) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The 4337:

Ferri N, Tibolla G, Pirillo A, Cipollone F, Mezzetti A, Pacia S, et al. (February 2012). "Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels".

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Shibata N, Ohnuma T, Higashi S, Higashi M, Usui C, Ohkubo T, et al. (December 2005). "No genetic association between PCSK9 polymorphisms and Alzheimer's disease and plasma cholesterol level in Japanese patients".

3899:"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" 1862:, 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 3789: 4512: 1790:

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).

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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.

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Pisciotta L, Priore Oliva C, Cefalù AB, Noto D, Bellocchio A, Fresa R, et al. (June 2006). "Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia".

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Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, Subashi TA, et al. (May 2007). "Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia".

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of 24 clinical trials has shown that monoclonal antibodies against PCSK9 can reduce cholesterol, cardiac events and all-cause mortality. The most recent guidelines for cholesterol management from the

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expressed in the brain. 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

1882:. 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. 4757:

Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH (February 2005). "Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9".

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Durairaj A, Sabates A, Nieves J, Moraes B, Baum S (August 2017). "Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Its Inhibitors: a Review of Physiology, Biology, and Clinical Data".

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Berger JM, Vaillant N, Le May C, Calderon C, Brégeon J, Prieur X, et al. (March 2015). "PCSK9-deficiency does not alter blood pressure and sodium balance in mouse models of hypertension".

3750:"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" 7017:

Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, et al. (March 2004). "A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree".

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Zhang L, Song K, Zhu M, Shi J, Zhang H, Xu L, Chen Y (August 2016). "Proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism, atherosclerosis and ischemic stroke".

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Chen YQ, Troutt JS, Konrad RJ (May 2014). "PCSK9 is present in human cerebrospinal fluid and is maintained at remarkably constant concentrations throughout the course of the day".

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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

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Naureckiene S, Ma L, Sreekumar K, Purandare U, Lo CF, Huang Y, et al. (December 2003). "Functional characterization of Narc 1, a novel proteinase related to proteinase K".

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Musunuru K, Chadwick AC, Mizoguchi T, Garcia SP, DeNizio JE, Reiss CW, et al. (May 2021). "In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates".

1750:, with a local effect that can regulate vascular homeostasis and atherosclerosis. Accordingly, it is now very clear that PCSK9 has pro-atherosclerotic effects and regulates 2769: 404: 303: 3793: 1850:

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

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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

5703:"Impact of early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors in patients with acute coronary syndrome: A systematic review meta-analysis" 5347: 6366:"Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1α protein expression through the ubiquitin-proteasome degradation pathway" 5869:

Shan L, Pang L, Zhang R, Murgolo NJ, Lan H, Hedrick JA (October 2008). "PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide".

4513:"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" 2068:

that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides.

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Wu CY, Tang ZH, Jiang L, Li XF, Jiang ZS, Liu LS (January 2012). "PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3 pathway".

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Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, et al. (June 2003). "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia".

2597: 1658:. It is expressed mainly in liver, intestine, kidney, skin and the central nervous system. After being processed in the ER, PCSK9 co-localizes with the protein 4191:"Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia" 6312:"Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine" 6054:"Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia" 4561:

Robinson JG (August 2016). "Nonstatins and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Role in Non-Familial Hypercholesterolemia".

2046: 1126: 1107: 226: 3041: 1669: 5753: 1492: 1474:, were approved as once every two week injections, by the U.S. Food and Drug Administration in 2015 for lowering LDL-particle concentrations when 4722:

Norata GD, Tibolla G, Catapano AL (August 2014). "PCSK9 inhibition for the treatment of hypercholesterolemia: promises and emerging challenges".

2790: 2358:"Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials" 2168: 2150: 5029:

Norata GD, Pirillo A, Ammirati E, Catapano AL (January 2012). "Emerging role of high density lipoproteins as a player in the immune system".

2252: 6825:"Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response" 7135: 6061: 2549:

Joseph L, Robinson JG (2015). "Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition and the Future of Lipid Lowering Therapy".

6217: 1835:). Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease. 5348:"Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease" 2551: 2531: 4976:

Magnasco L, Sepulcri C, Antonello RM, Di Bella S, Labate L, Luzzati R, et al. (2022). "The Role of PCSK9 in Infectious Diseases".

2193:"The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation" 1731:(HCHOLA3). The mutations increase its protease activity, reducing LDLR levels and preventing the uptake of cholesterol into the cells. 390: 6593:"NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol" 3350:"Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants" 1333: 1326: 6984:"Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia" 4175: 3706:"Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents" 367: 3606:"Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets" 2013:

increases expression of the LDLR and decreases circulating total cholesterol levels in mice. A locked nucleic acid reduced PCSK9

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now provide guidance for when PCSK9 inhibitors should be considered, particularly focusing on cases in which maximally tolerated

1520: 3817:"Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk" 1831:

Several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called

1524: 6628:"Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells" 6243: 4004:"Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes" 3354: 3207: 2998: 2137: 2116: 1504: 2674:"PCSK9 inhibitor access barriers-issues and recommendations: Improving the access process for patients, clinicians and payers" 1978: 1508: 2133: 1969:). As of July 2015, the EU approved these drugs including Evolocumab/Amgen according to Medscape news agency report. A 289: 264: 61: 5820:

Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, et al. (January 2014).

2304: 1909: 1728: 2112: 6084:"Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates" 5947:"A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo" 4843:"Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial" 1839: 1548: 206: 6698:

Leren TP (May 2004). "Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia".

3955:"Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G" 1680:

As a negative post-translational regulator of the low-density lipoprotein receptor (LDLR), PCSK9 plays a major role in

1859: 6244:"VERVE-101: CRISPR-Based Gene Editing Therapy Shows Promise in Reducing LDL-C and PCSK9 Levels in Patients With HeFH" 4155: 403: 302: 5308:"Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels" 4683:"Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis" 2057:

A vaccine that targets PCSK9 has been developed to treat high LDL-particle concentrations. The vaccine uses a VLP (

1974: 6737:"Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype" 396: 295: 4232:"Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in the Brain and Relevance for Neuropsychiatric Disorders" 2881:"Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study" 2483: 2010: 1966: 1926: 1893: 1450:

and other cell membranes, binds and initiates ingestion of LDL-particles from extracellular fluid into cells and

5906:"Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice" 6417:"The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials" 3203:"Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein" 1171: 214: 6790:"Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice" 4927:"Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9)" 2088:. It has been speculated that this action contributes to the ability of berberine to lower serum cholesterol. 1809:

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

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PCSK9 is ubiquitously expressed in many tissues and cell types. PCSK9 binds to and degrades the receptor for

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denied by insurance providers. As a result, pharmaceutical manufacturers lowered the prices of these drugs.

1431: 1424: 1152: 3049: 2725:"Association of Prior Authorization and Out-of-pocket Costs With Patient Access to PCSK9 Inhibitor Therapy" 2001:

Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.

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that bind to and inhibit PCSK9 near the catalytic domain were in clinical trials as of 2014. These include

4290:"Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering" 2644: 1904:

reaching market slightly later. Prices were very high, inhibiting adoption. The drugs are approved by the

1858:, it is plausible that these drugs may also reduce the risk of such diseases. Clinical studies, including 1851: 1516: 6889:"Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9" 6006:"PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates" 4598:"Erratum to: Efficacy and Safety of the PCSK9 Inhibitor Evolocumab in Patients with Mixed Hyperlipidemia" 3858:"Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia" 3511:

Gustafsen C, Kjolby M, Nyegaard M, Mattheisen M, Lundhede J, Buttenschøn H, et al. (February 2014).

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Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, et al. (August 2008).

1938: 1887: 1855: 1655: 1496: 1408: 6550:"Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia" 2191:

Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, et al. (February 2003).

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Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. (January 2017).

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Lo Surdo P, Bottomley MJ, Calzetta A, Settembre EC, Cirillo A, Pandit S, et al. (December 2011).

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Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Ørum H, et al. (May 2010). Deb S (ed.).

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Stein EA, Raal FJ (December 2014). "New therapies for reducing low-density lipoprotein cholesterol".

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Lopez D (2008). "Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia".

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Schmidt AF, Carter JL, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, Casas JP (October 2020).

3311: 3256:"Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH" 2678: 2058: 2042: 2030: 2025: 2017:

levels in mice. Initial clinical trials showed positive results of ALN-PCS, which acts by means of

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Bottomley MJ, Cirillo A, Orsatti L, Ruggeri L, Fisher TS, Santoro JC, et al. (January 2009).

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Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM (April 2007).

5615: 5572: 5449: 5138: 5095: 5011: 4782: 4543: 4398: 4160: 3391: 3176: 3023: 2960: 2650: 2459: 2277: 1533: 1466:. Agents that block PCSK9 can lower LDL particle concentrations. The first two PCSK9 inhibitors, 238: 6261:

Crossey E, Amar MJ, Sampson M, Peabody J, Schiller JT, Chackerian B, Remaley AT (October 2015).

5635:"PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease" 4097:"Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor" 1309: 1288: 1262: 1241: 197:, proprotein convertase subtilisin/kexin type 9, FH3, HCHOLA3, LDLCQ1, NARC-1, NARC1, PC9, FHCL3 6823:

Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, et al. (December 2005).

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Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, et al. (November 2005).

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or protective in the development of the nervous system. PCSK9 levels have been detected in the

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In addition to its lipoprotein synthetic and pro-atherosclerotic effects, PCSK9 is involved in

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Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, et al. (August 2004).

6875: 6846: 6811: 6776: 6715: 6678: 6649: 6614: 6571: 6536: 6497: 6458:"Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation" 6438: 6397: 6343: 6292: 6191: 6123: 6035: 6004:

Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, et al. (February 2012).

5986: 5927: 5886: 5851: 5802: 5734: 5664: 5607: 5564: 5525: 5484: 5441: 5406: 5329: 5288: 5229: 5194: 5130: 5087: 5046: 5003: 4958: 4907: 4872: 4823: 4802:"A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction" 4774: 4739: 4704: 4663: 4627: 4578: 4535: 4493: 4447: 4390: 4355: 4319: 4263: 4212: 4136: 4077: 4033: 3984: 3928: 3879: 3838: 3771: 3727: 3686: 3637: 3586: 3557:"Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9)" 3534: 3493: 3452: 3383: 3330: 3287: 3236: 3168: 3015: 2952: 2912: 2858: 2756: 2705: 2616: 2568: 2512: 2451: 2389: 2331: 2269: 2232: 1630: 1613:

The solved structure of PCSK9 reveals four major components in the pre-processed protein: the

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