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| __NOTOC__
| | #REDIRECT [[PCSK9]] |
| [[File:PCSK9.png|200px|thumb|right|Structure of the PCSK9 protein]] | |
| {{SI}}
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| {{CMG}}; {{AE}} {{AO}}
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| ==Overview==
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| Increased low-density lipoprotein cholesterol (LDL-C) levels in the plasma is associated with the development and progression of [[atherosclerosis]] and associated diseases such as [[myocardial infarction]] and [[stroke]]. LDL receptors, which are responsible for clearing LDL-C from the circulation, gets recycled back into the plasma membrane in order to bind more LDL-C. A novel approach to lipid management focuses on inhibiting a serine protease, PCSK9, which is involved in the degradation of LDL receptors subsequently preventing the binding of new LDLs to be cleared from the circulation.
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| ==Historical Perspective==
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| The role of PCSK9 was first discovered in 2003 when the cause of [[familial hypercholesterolemia]] in some french families was found to be associated with a 'gain of function' mutation of PCSK9 gene.<ref name=abifadel>{{cite journal | author = Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C | title = Mutations in PCSK9 cause autosomal dominant hypercholesterolemia | journal = Nat. Genet. | volume = 34 | issue = 2 | pages = 154–6 | year = 2003 | month = June|pmid = 12730697 | doi = 10.1038/ng1161 }}</ref> Two years later, a causative association was found between 'loss of function mutations in PCSK9 and low LDL-C levels in 2% of the African-American population but rare in European Americans (<0.1%), and were associated with a 40% reduction in plasma levels of LDL cholesterol.<ref name="Cohen-2005">{{Cite journal | last1 = Cohen | first1 = J. | last2 = Pertsemlidis | first2 = A. | last3 = Kotowski | first3 = IK. | last4 = Graham | first4 = R. | last5 = Garcia | first5 = CK. | last6 = Hobbs | first6 = HH. | title = Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. | journal = Nat Genet | volume = 37 | issue = 2 | pages = 161-5 | month = Feb | year = 2005 | doi = 10.1038/ng1509 | PMID = 15654334 }}</ref>
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| ==Structure, Function and Regulation==
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| ====Structure====
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| Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is a serine protease that in humans is encoded by the PCSK9 [[gene]].<ref name=seidah>{{cite journal | author = Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M | title = The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 3 | pages = 928–33 | year = 2003 | month = February | pmid = 12552133 | pmc = 298703 |doi = 10.1073/pnas.0335507100 }}</ref> PCSK9 encodes a 692 amino acid protein that is expressed mainly in the liver, intestine, and kidney.<ref name="Zaid-2008">{{Cite journal | last1 = Zaid | first1 = A. | last2 = Roubtsova | first2 = A. | last3 = Essalmani | first3 = R. | last4 = Marcinkiewicz | first4 = J. | last5 = Chamberland | first5 = A. | last6 = Hamelin | first6 = J. | last7 = Tremblay | first7 = M. | last8 = Jacques | first8 = H. | last9 = Jin | first9 = W. | title = Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. | journal = Hepatology | volume = 48 | issue = 2 | pages = 646-54 | month = Aug | year = 2008 | doi = 10.1002/hep.22354 | PMID = 18666258 }}</ref> This gene encodes a [[proprotein convertase]] belonging to the [[proteinase K]] subfamily of the secretory subtilase family. The encoded protein is synthesized as a soluble [[zymogen]] that undergoes autocatalytic intramolecular processing in the [[endoplasmic reticulum]]. The protein may function as a [[proprotein convertase]]. This protein plays a major regulatory role in [[cholesterol]] homeostasis.
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| ====Function====
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| PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the [[low-density lipoprotein]] receptor (LDLR), inducing LDLR degradation in the lysosomes. Reduced LDL receptor levels result in decreased metabolism of [[low-density lipoproteins]] (LDL), which could lead to hypercholesterolemia.<ref name=uendo>*{{cite web | url =http://www.uendocrine.com/presentations/hyperlipidemia/the-evolving-role-of-pcsk9-modulation-in-the-regulation-of-ldl-cholesterol | title = The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol | author = | authorlink = | coauthors = | date = 2012-11-11 }}</ref> PCSK9 also have a role in the differentiation of cortical neurons,<ref name=seidah>{{cite journal |author = Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M | title = The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 3 | pages = 928–33 | year = 2003 | month = February | pmid = 12552133 | pmc = 298703 | doi = 10.1073/pnas.0335507100 }}</ref> and may also modulate apoB-containing lipoprotein production, independently
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| of the LDL receptors.<ref name="Sun-2012">{{Cite journal | last1 = Sun | first1 = H. | last2 = Samarghandi | first2 = A. | last3 = Zhang | first3 = N. | last4 = Yao | first4 = Z. | last5 = Xiong | first5 = M. | last6 = Teng | first6 = BB. | title = Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. | journal = Arterioscler Thromb Vasc Biol | volume = 32 | issue = 7 | pages = 1585-95 | month = Jul | year = 2012 | doi = 10.1161/ATVBAHA.112.250043 | PMID = 22580899 }}</ref>
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| ====Regulation====
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| PCSK9 and LDL recptors are chiefly regulated via the transcription factor sterol-responsive element-binding protein 2 (SREBP2), a pathway also induced by statins,<ref name="Lambert-2007">{{Cite journal | last1 = Lambert | first1 = G. | title = Unravelling the functional significance of PCSK9. | journal = Curr Opin Lipidol | volume = 18 | issue = 3 | pages = 304-9 | month = Jun | year = 2007 | doi = 10.1097/MOL.0b013e3281338531 | PMID = 17495605 }}</ref> and an experimental [[resistin]]<ref name="Melone-2012">{{Cite journal | last1 = Melone | first1 = M. | last2 = Wilsie | first2 = L. | last3 = Palyha | first3 = O. | last4 = Strack | first4 = A. | last5 = Rashid | first5 = S. | title = Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. | journal = J Am Coll Cardiol | volume = 59 | issue = 19 | pages = 1697-705 | month = May | year = 2012 | doi = 10.1016/j.jacc.2011.11.064 | PMID = 22554600 }}</ref> which is an adipose-tissue derived adipokine. Another regulator of the PCSK9 gene expression is the hepatic nuclear factor 1 alpha (HNF1a), a transcription factor activated in the liver cells.<ref name="Dong-2010">{{Cite journal | last1 = Dong | first1 = B. | last2 = Wu | first2 = M. | last3 = Li | first3 = H. | last4 = Kraemer | first4 = FB. | last5 = Adeli | first5 = K. | last6 = Seidah | first6 = NG. | last7 = Park | first7 = SW. | last8 = Liu | first8 = J. | title = Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. | journal = J Lipid Res | volume = 51 | issue = 6 | pages = 1486-95 | month = Jun | year = 2010 | doi = 10.1194/jlr.M003566 | PMID = 20048381 }}</ref> PCSK9 has medical significance because it acts in cholesterol synthesis. Drugs that block PCSK9 can lower cholesterol, and are beginning Phase III clinical trials to see if they can improve outcomes in heart disease.<ref name=pollack>{{cite web | url =http://www.nytimes.com/2012/11/06/business/new-drugs-for-lipids-set-off-race.html | title = New Drugs for Lipids Set Off Race | author = Pollack A | date = November 5, 2012 | work = | publisher = New York Times }}</ref>
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| ==PCSK9 Inhibitors==
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| ===Natural===
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| * [[Annexin A2]] (AnxA2) - This is an endogenous compound that binds to the C-terminal domain of PCSK9 thereby preventing the interaction of PCSK9 and LDL receptors mostly in the extrahepatic tissues. It has been proven as a functional inhibitor of PCSK9.<ref name="Seidah-2012">{{Cite journal | last1 = Seidah | first1 = NG. | last2 = Poirier | first2 = S. | last3 = Denis | first3 = M. | last4 = Parker | first4 = R. | last5 = Miao | first5 = B. | last6 = Mapelli | first6 = C. | last7 = Prat | first7 = A. | last8 = Wassef | first8 = H. | last9 = Davignon | first9 = J. | title = Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. | journal = PLoS One | volume = 7 | issue = 7 | pages = e41865 | month = | year = 2012 | doi = 10.1371/journal.pone.0041865 | PMID = 22848640 }}</ref>
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| * [[Furin]] and PC5/6A - These two proprotein convertases act through the proteolytic cleavage of the PCSK9 protein between the R<sub>218</sub> and Q<sub>219</sub> residues resulting in a defective enzyme. Furin was shown to regulate PCSK9 mRNA levels in hepatocytes.<ref name="pmid21147780">{{cite journal| author=Essalmani R, Susan-Resiga D, Chamberland A, Abifadel M, Creemers JW, Boileau C et al.| title=In vivo evidence that furin from hepatocytes inactivates PCSK9. | journal=J Biol Chem | year= 2011 | volume= 286 | issue= 6 | pages= 4257-63 | pmid=21147780 | doi=10.1074/jbc.M110.192104 | pmc=PMC3039354 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21147780 }} </ref>
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| ===Pharmacologic===
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| Drugs can inhibit PCSK9, and lower cholesterol much more than available drugs. It is biologically plausible that this would also lower heart attacks and other diseases caused by raised cholesterol. Studies with humans, including phase III clinical trials are now underway to find out whether PCSK9 inhibition actually does lower disease, with acceptable side effects.<ref name=lopez>{{cite journal | author = Lopez D|title = Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia | journal = Drug News Perspect. | volume = 21|issue = 6 | pages = 323–30 | year = 2008 | pmid = 18836590 | doi = 10.1358/dnp.2008.21.6.1246795 }}</ref><ref name=steinberg>{{cite journal|author = Steinberg D, Witztum JL | title = Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 24 | pages = 9546–7 | year = 2009 | month = June | pmid = 19506257 | pmc = 2701045|doi = 10.1073/pnas.0904560106 }}</ref><ref name=mayer>{{cite journal | author = Mayer G, Poirier S, Seidah NG | title = Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels | journal = J. Biol. Chem. | volume = 283|issue = 46 | pages = 31791–801 | year = 2008 | month = November | pmid = 18799458 | doi = 10.1074/jbc.M805971200 }}</ref><ref name=bms>{{cite web | url = http://www.fiercebiotech.com/press-releases/bristol-myers-squibb-selects-isis-drug-targeting-pcsk9-development-candidate-preventi| title = Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease | author = | authorlink = | coauthors = | date = 2008-04-08 | format = | work = Press Release | publisher = FierceBiotech | pages =| language = | archiveurl = | archivedate = | quote = | accessdate = 2010-09-18 }}</ref>
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| ====Monoclonal antibodies====
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| A number of [[monoclonal antibodies]] that bind to PCSK9 near the catalytic domain that interact with the LDL receptors, and hence inhibit the function of PCSK9 are currently in clinical trials. These include:
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| * AMG145 by [[Amgen]]
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| * 1D05-IgG2 by [[Merck & Co.]]
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| * SAR236553/REGN727 by Sanofi-[[Aventis]]/[[Regeneron]].<ref name=lambert>{{cite journal | author = Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK | title = The PCSK9 decade | journal = J. Lipid Res. | volume = 53 | issue = 12 | pages = 2515–24 | year = 2012 | month = December | pmid = 22811413 | doi = 10.1194/jlr.R026658 | url = | pmc = 3494258 }}</ref>
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| * RN316 by Pfizer
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| * Additional drugs by Roche/Genentech and Lilly
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| ====Peptide mimics====
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| Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.<ref name=shan />
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| === Gene silencing ===
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| PCSK9 [[antisense oligonucleotide]] from [[Isis Pharmaceuticals]] has been shown to increase expression of the LDLR and decrease circulating total cholesterol levels in mice.<ref name=graham>{{cite journal | author = Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM | title = Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice| journal = J. Lipid Res. | volume = 48 | issue = 4 | pages = 763–7 | year = 2007 | month = April | pmid = 17242417 | doi = 10.1194/jlr.C600025-JLR200 }}</ref> A locked nucleic acid from [[Santaris Pharma]] reduced PCSK9 mRNA levels in mice.<ref name=gupta>{{cite journal | author = Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Ørum H, Elmén J, Seidah NG, Straarup EM | title = A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo | journal = PLoS ONE | volume = 5 |issue = 5 | pages = e10682 | year = 2010 | pmid = 20498851 | pmc = 2871785 | doi = 10.1371/journal.pone.0010682 | url = | editor1-last = Deb| editor1-first = Sumitra }}</ref><ref name=lindholm>{{cite journal | author = Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, Rosenbohm C, Ørum H, Straarup EM, Koch T | title = PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates | journal = Mol. Ther. | volume = 20 | issue = 2 | pages = 376–81 | year = 2012 | month = February | pmid = 22108858 | pmc = 3277239 | doi = 10.1038/mt.2011.260 }}</ref>
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| [[Alnylam Pharmaceuticals]] has shown in initial clinical trials positive results of ALN-PCS which acts by means of [[RNA interference]], as an effective means of PCSK9 inhibition.<ref name=alnypharm>{{cite web | url = http://phx.corporate-ir.net/phoenix.zhtml?c=148005&p=irol-newsArticle2&ID=1644329&highlight= | title = Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia | author = | authorlink = | coauthors = | date = 2011-01-04 | format = | work = Press Release | publisher = BusinessWire | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2011-01-04 }}</ref><ref name=frank>{{cite journal | author = Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, Gamba-Vitalo C, Hadwiger P, Jayaraman M, John M, Jayaprakash KN, Maier M, Nechev L, Rajeev KG, Read T, Röhl I, Soutschek J, Tan P, Wong J, Wang G, Zimmermann T, de Fougerolles A, Vornlocher HP, Langer R, Anderson DG, Manoharan M, Koteliansky V, Horton JD, Fitzgerald K | title = Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates| journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 33 | pages = 11915–20 | year = 2008 | month = August | pmid = 18695239 |pmc = 2575310 | doi = 10.1073/pnas.0805434105 }}</ref>
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| == Clinical significance ==
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| Variants of PCSK9 can reduce or increase circulating cholesterol.
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| LDL cholesterol is removed from the blood when it binds to LDL receptors on the surface of liver cells, and is taken inside the cells. When PCSK9 binds to the LDL receptor, the receptor is destroyed along with the LDL. But if PCSK9 does not bind, the receptor can return to the surface of the cell and remove more cholesterol.<ref name=pollack>{{cite web | url = http://www.nytimes.com/2012/11/06/business/new-drugs-for-lipids-set-off-race.html | title = New Drugs for Lipids Set Off Race | author = Pollack A | date = November 5, 2012 | work = | publisher = New York Times }}</ref>
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| Some variants, which only reduce cholesterol by 15% in whites, are associated with a reduction in coronary heart disease by 50%.
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| Other variants are associated with a rare autosomal dominant [[familial hypercholesterolemia]] (HCHOLA3).<ref name=entrez>{{cite web | title = Entrez Gene: PCSK9 proprotein convertase subtilisin/kexin type 9| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=255738| accessdate = }}</ref><ref name=abifadel>{{cite journal | author = Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C | title = Mutations in PCSK9 cause autosomal dominant hypercholesterolemia | journal = Nat. Genet. | volume = 34 | issue = 2 | pages = 154–6 | year = 2003 | month = June| pmid = 12730697 | doi = 10.1038/ng1161 }}</ref><ref name=dubuc>{{cite journal | author = Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A | title = Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia | journal = Arterioscler. Thromb. Vasc. Biol. | volume = 24 | issue = 8 | pages = 1454–9 | year = 2004 | month = August | pmid = 15178557 | doi = 10.1161/01.ATV.0000134621.14315.43 }}</ref> The mutations increase its protease activity, reducing [[Low-density lipoprotein|LDL]] receptor levels and preventing the uptake of cholesterol into the cells.<ref name=abifadel />
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| ==References==
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| {{Reflist|2}}
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