Beyond LDL Cholesterol, a New Role for PCSK9

Abstract

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 30, No. 7Beyond LDL Cholesterol, a New Role for PCSK9 Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBBeyond LDL Cholesterol, a New Role for PCSK9 Omar N. Akram, Adeline Bernier, Francine Petrides, Gida Wong and Gilles Lambert Omar N. AkramOmar N. Akram From the Lipid Research Group, The Heart Research Institute, Sydney, Australia (O.N.A., A.B., F.P., G.W., G.L.); University of Sydney Medical School, Sydney, Australia (O.N.A.); École Normale Supérieure, Rue d'Ulm, Paris, France (A.B.); Queen Elizabeth Hospital, Hong Kong, China (G.W.); Université de Nantes, Faculté de Médecine, Nantes, France (G.L.). Search for more papers by this author , Adeline BernierAdeline Bernier From the Lipid Research Group, The Heart Research Institute, Sydney, Australia (O.N.A., A.B., F.P., G.W., G.L.); University of Sydney Medical School, Sydney, Australia (O.N.A.); École Normale Supérieure, Rue d'Ulm, Paris, France (A.B.); Queen Elizabeth Hospital, Hong Kong, China (G.W.); Université de Nantes, Faculté de Médecine, Nantes, France (G.L.). Search for more papers by this author , Francine PetridesFrancine Petrides From the Lipid Research Group, The Heart Research Institute, Sydney, Australia (O.N.A., A.B., F.P., G.W., G.L.); University of Sydney Medical School, Sydney, Australia (O.N.A.); École Normale Supérieure, Rue d'Ulm, Paris, France (A.B.); Queen Elizabeth Hospital, Hong Kong, China (G.W.); Université de Nantes, Faculté de Médecine, Nantes, France (G.L.). Search for more papers by this author , Gida WongGida Wong From the Lipid Research Group, The Heart Research Institute, Sydney, Australia (O.N.A., A.B., F.P., G.W., G.L.); University of Sydney Medical School, Sydney, Australia (O.N.A.); École Normale Supérieure, Rue d'Ulm, Paris, France (A.B.); Queen Elizabeth Hospital, Hong Kong, China (G.W.); Université de Nantes, Faculté de Médecine, Nantes, France (G.L.). Search for more papers by this author and Gilles LambertGilles Lambert From the Lipid Research Group, The Heart Research Institute, Sydney, Australia (O.N.A., A.B., F.P., G.W., G.L.); University of Sydney Medical School, Sydney, Australia (O.N.A.); École Normale Supérieure, Rue d'Ulm, Paris, France (A.B.); Queen Elizabeth Hospital, Hong Kong, China (G.W.); Université de Nantes, Faculté de Médecine, Nantes, France (G.L.). Search for more papers by this author Originally published1 Jul 2010https://doi.org/10.1161/ATVBAHA.110.209007Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30:1279–1281Elevated low-density lipoprotein cholesterol (LDLC) levels in the plasma is the most important causative factor of atherosclerosis and associated ischemic cardiovascular diseases. The LDL receptor (LDLR) is the preferential pathway through which LDLs are cleared from the circulation. LDLs bound to the LDLR are internalized into clathrin-coated pits and subsequently undergo lysosomal degradation, whereas the LDLR is recycled back to the plasma membrane.See accompanying article on page 1333Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with elevated LDL levels and premature coronary heart disease. FH is caused primarily by mutations of the LDLR or of apolipoprotein B100 (apoB100), the protein component of LDL that interacts with the LDLR. In 2003, “gain of function” mutations on a newly identified gene, proprotein convertase subtilisin/kexin type 9 (PCSK9), were associated with FH. In 2005, a causative association was established between “loss of function” mutations in PCSK9 and low LDLC levels in 2% of the African-American population. The coronary heart disease risk in these individuals was reduced by 88%. As a result of these landmark studies (reviewed in Reference 1), PCSK9 became the subject of intensive research to discover the underlying mechanisms.PCSK9 is a serine protease mainly expressed in the liver and the intestine. It acts by reducing the amount of LDLR in hepatocytes. This was demonstrated in vitro and in mouse models and inferred by genetic studies in patients with PCSK9 mutations (reviewed in Reference 2). In brief, PCSK9 enzymatic activity permits its intracellular maturation, followed by secretion (Figure). Circulating PCSK9 binds the LDLR on the cell surface and is subsequently cointernalized together with the LDLR. This promotes the degradation of the receptor in the lysosome, rather than recycling to the plasma membrane. PCSK9 can also bind the LDLR intracellularly.3 Thus, by virtue of its role as a major inhibitor of the LDLR, PCSK9 has emerged as a hot new drug target to treat hypercholesterolemia and coronary heart disease. Download figureDownload PowerPointFigure. After undergoing autocleavage in the endoplasmic reticulum (ER), the prodomain of PCSK9 remains associated with the catalytic domain in the Golgi, and the complex is secreted into the plasma. I, Circulating PCSK9 binds the LDLR, is internalized, and targets the receptor for lysosomal degradation, rather than recycling to the membrane. An alternative pathway of PCSK9 induced LDLR degradation, in which PCSK9 binds the LDLR in the Golgi has been proposed. ARH, adaptor protein.PCSK9 inhibition has been intensively studied in cell-based systems. A peptide, which mimics the interaction domain of the LDLR with PCSK9, can inhibit PCSK9 binding to the LDLR and prevent its degradation.4 Likewise, an anti-PCSK9 antibody5 and an anti-PCSK9 antigen binding fragment6 disrupt the interaction between PCSK9 and the LDLR, thus restoring cellular LDL-uptake. In vivo, PCSK9 has been inhibited using antisense oligonucleotides7 or small interfering RNA (siRNA).8 These treatments dramatically increase hepatic LDLR and lower plasma LDLC in rodents and monkeys. Another approach has involved infusions of humanized anti-PCSK9 antibodies.9 A single injection of these antibodies reduced LDLC by 80% in monkeys. This study also showed that anti-PCSK9 antibodies act synergistically with statins to increase LDLR cell surface expression, indicating that blocking PCSK9 in statin-treated patients will most likely further reduce their LDLC levels. Thus, PCSK9 inhibitors should prove invaluable for patients at risk of developing recurrent cardiovascular events despite aggressive statin treatment and in patients with FH.In that respect, the D374Y-PCSK9 gain of function missense mutation is at the origin of an extremely severe FH phenotype, particularly hard to treat with statins. Carriers of the D374Y-PCSK9 mutation are affected 10 years earlier than other FH patients by premature coronary heart disease.10 This mutant was found to bind the LDLR with a 5- to 30-fold higher affinity compared with wild-type PCSK9, by allowing a hydrogen bond to form between the PCSK9 and the peptide domain of the LDLR.11The study by Herbert et al12 in this issue of Arteriosclerosis, Thrombosis and Vascular Biology demonstrates that the D374Y-PCSK9 mutation causes atherosclerosis as a result of (1) impaired LDL clearance, as well as (2) increased secretion of apoB-containing lipoproteins. In this study, mice lines expressing human PCSK9 (wild type and D374Y) at physiological levels were generated. Transgenes expression was restricted almost exclusively to the liver, and human PCSK9 was detected in the plasma of these animals. As anticipated, plasma cholesterol levels were more elevated in D374Y-PCSK9 transgenics, followed by wild-type PCSK9 transgenics, compared with control mice, and this phenotype was exacerbated on a cholesterol-rich diet. All transgenics had lower hepatic LDLR expression than controls. The plasma lipoprotein profile of wild-type PCSK9 trangenics was characterized by an increase in LDL levels. That of D374Y-PCSK9 transgenics was characterized by an even sharper increase in LDL, as well as by the presence of large very-low-density lipoprotein (VLDL)/intermediate-density lipoprotein particles in the plasma, resulting from an increased production of triglyceride-rich lipoproteins. After 15 weeks on a cholesterol-rich diet, only the D374Y-PCSK9 transgenic mice displayed aortic atherosclerotic lesions. To date, this is the only genetically engineered PCSK9 animal model in which atherosclerosis has been assessed. The D374Y-PCSK9 transgenic mice should prove useful to test the antiatherogenic potential of PCSK9 inhibitors, either alone or in combination with a statin.Another merit of this study12 is to unravel a role for PCSK9 on lipoprotein metabolism that does not apparently involve the LDLR. This has been a controversy for some time, depending on the animal model or experimental settings. Because PCSK9 knockout and LDLR/PCSK9 double knockout mice have the same lipoprotein profile, it was concluded that PCSK9 regulates cholesterol homeostasis exclusively via the LDLR.13 But PCSK9 knockout mice secrete larger chylomicrons and less apoB, and they clear chylomicron remnants faster than control animals.14 ApoB100 secretion from primary hepatocytes of PCSK9 knockouts is also reduced.15 Overproduction of apoB100 was reported in FH patients carrying the S127R-PCSK9 gain of function mutation, as well as in hepatoma cells expressing D374Y-PCSK9.16,17 In addition, PCSK9 overexpression was associated with increased VLDL hepatic output in mice on fasting,18 and we have recently reported that fenofibrate concomitantly decrease serum PCSK9 and VLDL particle concentration in statin-treated type 2 diabetics.19 Lately, 2 studies have indicated that serum triglyceride levels correlate with circulating PCSK9 in humans.20,21Therefore, beside the well-established role of PCSK9, as a bona fide LDLR inhibitor and prime modulator of plasma LDL levels, there is mounting evidence that PCSK9 plays a role in triglyceride-rich lipoprotein metabolism, at least in certain pathophysiological conditions (fasting and gavage), and for 2 gain of function mutants (D374Y and S127R). Whether the LDLR is involved in part, directly or indirectly, in these metabolic pathways certainly merits further investigation.DisclosuresNone.FootnotesCorrespondence to Prof Gilles Lambert, The Heart Research Institute, 7 Eliza Street, Newtown, NSW 2042, Australia. E-mail [email protected] References 1 Lambert G. Unravelling the functional significance of PCSK9. Curr Opin Lipidol. 2007; 18: 304–309.CrossrefMedlineGoogle Scholar2 Lambert G, Charlton F, Rye KA, Piper DE. Molecular basis of PCSK9 function. Atherosclerosis. 2009; 203: 1–7.CrossrefMedlineGoogle Scholar3 Poirier S, Mayer G, Poupon V, McPherson PS, Desjardins R, Ly K, Asselin MC, Day R, Duclos FJ, Witmer M, Parker R, Prat A, Seidah NG. Dissection of the endogenous cellular pathways of PCSK9-induced LDL receptor degradation: evidence for an intracellular route. J Biol Chem. 2009; 284: 28856–28864.CrossrefMedlineGoogle Scholar4 Shan L, Pang L, Zhang R, Murgolo NJ, Lan H, Hedrick JA. PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide. Biochem Biophys Res Commun. 2008; 375: 69–73.CrossrefMedlineGoogle Scholar5 Duff CJ, Scott MJ, Kirby IT, Hutchinson SE, Martin SL, Hooper NM. Antibody-mediated disruption of the interaction between PCSK9 and the LDL receptor. Biochem J. 2009; 419: 577–584.CrossrefMedlineGoogle Scholar6 Ni YG, Condra JH, Orsatti L, Shen X, Di Marco S, Pandit S, Bottomley MJ, Ruggeri L, Cummings RT, Cubbon RM, Santoro JC, Ehrhardt A, Lewis D, Fisher TS, Ha S, Njimoluh L, Wood DD, Hammond HA, Wisniewski D, Volpari C, Noto A, Lo Surdo P, Hubbard B, Carfi A, Sitlani A. A PCSK9 C-terminal domain antibody antigen-binding fragment inhibits PCSK9 internalization and restores low density lipoprotein uptake. J Biol Chem. 2010; 285: 12882–12891.CrossrefMedlineGoogle Scholar7 Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM. Antisense inhibition of PCSK9 reduces serum LDL in hyperlipidemic mice. J Lipid Res. 2007; 48: 763–767.CrossrefMedlineGoogle Scholar8 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, Rohl 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. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci U S A. 2008; 105: 11915–11920.CrossrefMedlineGoogle Scholar9 Chan JC, Piper DE, Cao Q, Liu D, King C, Wang W, Tang J, Liu Q, Higbee J, Xia Z, Di Y, Shetterly S, Arimura Z, Salomonis H, Romanow WG, Thibault ST, Zhang R, Cao P, Yang XP, Yu T, Lu M, Retter MW, Kwon G, Henne K, Pan O, Tsai MM, Fuchslocher B, Yang E, Zhou L, Lee KJ, Daris M, Sheng J, Wang Y, Shen WD, Yeh WC, Emery M, Walker NP, Shan B, Schwarz M, Jackson SM. A PCSK9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A. 2009; 106: 9820–9825.CrossrefMedlineGoogle Scholar10 Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, van Heyningen C, Soutar AK. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol. 2005; 25: 2654–2660.LinkGoogle Scholar11 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, Carfi A. Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants. J Biol Chem. 2009; 284: 1313–1323.CrossrefMedlineGoogle Scholar12 Herbert B, Patel D, Waddington SN, Eden ER, McAleenan A, Sun XM, Soutar AK. Increased secretion of lipoproteins in transgenic mice expressing human D374Y PCSK9 under physiological genetic control. Arterioscler Thromb Vasc Biol. 2010; 1333–1339.Google Scholar13 Zaid A, Roubtsova A, Essalmani R, Marcinkiewicz J, Chamberland A, Hamelin J, Tremblay M, Jacques H, Jin W, Davignon J, Seidah NG, Prat A. PCSK9: hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology. 2008; 48: 646–654.CrossrefMedlineGoogle Scholar14 Le May C, Kourimate S, Langhi C, Chetiveaux M, Jarry A, Comera C, Collet X, Kuipers F, Krempf M, Cariou B, Costet P. PCSK9 null mice are protected from postprandial triglyceridemia. Arterioscler Thromb Vasc Biol. 2009; 29: 684–690.LinkGoogle Scholar15 Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, Hammer RE, Moon YA, Horton JD. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci U S A. 2005; 102: 5374–5379.CrossrefMedlineGoogle Scholar16 Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, Boileau C, Magot T, Krempf M. Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. Arterioscler Thromb Vasc Biol. 2004; 24: 1448–1453.LinkGoogle Scholar17 Sun XM, Eden ER, Tosi I, Neuwirth CK, Wile D, Naoumova RP, Soutar AK. Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Hum Mol Genet. 2005; 14: 1161–1169.CrossrefMedlineGoogle Scholar18 Lambert G, Jarnoux AL, Pineau T, Pape O, Chetiveaux M, Laboisse C, Krempf M, Costet P. Fasting induces hyperlipidemia in mice overexpressing PCSK9: lack of modulation of VLDL hepatic output by the LDL receptor. Endocrinology. 2006; 147: 4985–4995.CrossrefMedlineGoogle Scholar19 Chan DC, Hamilton SJ, Rye KA, Chew GT, Jenkins AJ, Lambert G, Watts GF. Fenofibrate concomitantly decreases serum PCSK9 and VLDL particle concentrations in statin-treated type 2 diabetic patients. Diabetes Obes Metab. doi:10.1111/j.1463-1326.2010.01229. x.Google Scholar20 Baass A, Dubuc G, Tremblay M, Delvin EE, O'Loughlin J, Levy E, Davignon J, Lambert M. Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents. Clin Chem. 2009; 55: 1637–1645.CrossrefMedlineGoogle Scholar21 Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab. 2009; 94: 2537–2543.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Song L, Zhao X, Chen R, Li J, Zhou J, Liu C, Zhou P, Wang Y, Chen Y, Zhao H and Yan H (2022) Association of PCSK9 with inflammation and platelet activation markers and recurrent cardiovascular risks in STEMI patients undergoing primary PCI with or without diabetes, Cardiovascular Diabetology, 10.1186/s12933-022-01519-3, 21:1, Online publication date: 1-Dec-2022. Coppinger C, Movahed M, Azemawah V, Peyton L, Gregory J and Hashemzadeh M (2022) A Comprehensive Review of PCSK9 Inhibitors, Journal of Cardiovascular Pharmacology and Therapeutics, 10.1177/10742484221100107, 27, (107424842211001), Online publication date: 1-Jan-2022. 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