{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T23:06:32Z","timestamp":1785539192659,"version":"3.56.0"},"reference-count":154,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP-136986"],"award-info":[{"award-number":["MOP-136986"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Microbial cell walls contain pathogenic lipids, including LPS in gram-negative bacteria, lipoteichoic acid in gram-positive bacteria, and phospholipomannan in fungi. These pathogen lipids are major ligands for innate immune receptors and figure prominently in triggering the septic inflammatory response. Alternatively, pathogen lipids can be cleared and inactivated, thus limiting the inflammatory response. Accordingly, biological mechanisms for sequestering and clearing pathogen lipids from the circulation have evolved. Pathogen lipids released into the circulation are initially bound by transfer proteins, notably LPS binding protein and phospholipid transfer protein, and incorporated into high-density lipoprotein particles. Next, LPS binding protein, phospholipid transfer protein, and other transfer proteins transfer these lipids to ApoB-containing lipoproteins, including low-density (LDL) and very-low-density lipoproteins and chylomicrons. Pathogen lipids within these lipoproteins and their remnants are then cleared from the circulation by the liver. Hepatic clearance involves the LDL receptor (LDLR) and possibly other receptors. Once absorbed by the liver, these lipids are then excreted in the bile. Recent evidence suggests pathogen lipid clearance can be modulated. Importantly, reduced proprotein convertase subtilisin\/kexin type 9 activity increases recycling of the LDLR and thereby increases LDLR on the surface of hepatocytes, which increases clearance by the liver of pathogen lipids transported in LDL. Increased pathogen lipid clearance, which can be achieved by inhibiting proprotein convertase subtilisin\/kexin type 9, may decrease the systemic inflammatory response to sepsis and improve clinical outcomes.<\/jats:p>","DOI":"10.1164\/rccm.201505-0876ci","type":"journal-article","created":{"date-parts":[[2015,8,7]],"date-time":"2015-08-07T14:47:58Z","timestamp":1438958878000},"page":"1275-1286","source":"Crossref","is-referenced-by-count":54,"title":["The Central Role of Proprotein Convertase Subtilisin\/Kexin Type 9 in Septic Pathogen Lipid Transport and Clearance"],"prefix":"10.1093","volume":"192","author":[{"given":"Keith R.","family":"Walley","sequence":"first","affiliation":[{"name":"Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon A.","family":"Francis","sequence":"additional","affiliation":[{"name":"Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Opal","sequence":"additional","affiliation":[{"name":"Infectious Disease Division, Memorial Hospital of Rhode Island and Alpert Medical School of Brown University, Providence, Rhode Island; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan A.","family":"Stein","sequence":"additional","affiliation":[{"name":"Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Russell","sequence":"additional","affiliation":[{"name":"Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H.","family":"Boyd","sequence":"additional","affiliation":[{"name":"Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,12,1]]},"reference":[{"key":"2026032100124908600_bib1","doi-asserted-by":"crossref","first-page":"3280","DOI":"10.1128\/IAI.71.6.3280-3284.2003","article-title":"Distribution and kinetics of lipoprotein-bound lipoteichoic acid","volume":"71","author":"Levels","year":"2003","journal-title":"Infect Immun"},{"key":"2026032100124908600_bib2","doi-asserted-by":"crossref","first-page":"30520","DOI":"10.1074\/jbc.274.43.30520","article-title":"The Candida albicans phospholipomannan is a family of glycolipids presenting phosphoinositolmannosides with long linear chains of beta-1,2-linked mannose residues","volume":"274","author":"Trinel","year":"1999","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib3","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1097\/CCM.0b013e31819267fb","article-title":"Molecular biology of inflammation and sepsis: a primer","volume":"37","author":"Cinel","year":"2009","journal-title":"Crit Care Med"},{"key":"2026032100124908600_bib4","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1042\/BST0390984","article-title":"Plasma PLTP (phospholipid-transfer protein): an emerging role in \u2018reverse lipopolysaccharide transport\u2019 and innate immunity","volume":"39","author":"Gautier","year":"2011","journal-title":"Biochem Soc Trans"},{"key":"2026032100124908600_bib5","first-page":"287","article-title":"Lipopolysaccharide (LPS) binding protein catalyzes binding of LPS to lipoproteins","volume":"392","author":"Wurfel","year":"1995","journal-title":"Prog Clin Biol Res"},{"key":"2026032100124908600_bib6","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.4049\/jimmunol.170.3.1399","article-title":"Lipopolysaccharide (LPS)-binding protein mediates LPS detoxification by chylomicrons","volume":"170","author":"Vreugdenhil","year":"2003","journal-title":"J Immunol"},{"key":"2026032100124908600_bib7","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1128\/IAI.73.4.2321-2326.2005","article-title":"Lipopolysaccharide is transferred from high-density to low-density lipoproteins by lipopolysaccharide-binding protein and phospholipid transfer protein","volume":"73","author":"Levels","year":"2005","journal-title":"Infect Immun"},{"key":"2026032100124908600_bib8","doi-asserted-by":"crossref","first-page":"12172","DOI":"10.1074\/jbc.271.21.12172","article-title":"Neutralization and transfer of lipopolysaccharide by phospholipid transfer protein","volume":"271","author":"Hailman","year":"1996","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib9","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.tem.2012.02.001","article-title":"Crosstalk between reverse cholesterol transport and innate immunity","volume":"23","author":"Azzam","year":"2012","journal-title":"Trends Endocrinol Metab"},{"key":"2026032100124908600_bib10","doi-asserted-by":"crossref","first-page":"9546","DOI":"10.1073\/pnas.0904560106","article-title":"Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels","volume":"106","author":"Steinberg","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100124908600_bib11","doi-asserted-by":"crossref","first-page":"7922","DOI":"10.1073\/pnas.91.17.7922","article-title":"Mode of action of anti-lipopolysaccharide-binding protein antibodies for prevention of endotoxemic shock in mice","volume":"91","author":"Gallay","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100124908600_bib12","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.imlet.2008.03.009","article-title":"Comparison of the immunostimulatory and proinflammatory activities of candidate Gram-positive endotoxins, lipoteichoic acid, peptidoglycan, and lipopeptides, in murine and human cells","volume":"118","author":"Kimbrell","year":"2008","journal-title":"Immunol Lett"},{"key":"2026032100124908600_bib13","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/j.1574-6968.2011.02260.x","article-title":"Location, synthesis and function of glycolipids and polyglycerolphosphate lipoteichoic acid in Gram-positive bacteria of the phylum Firmicutes","volume":"319","author":"Reichmann","year":"2011","journal-title":"FEMS Microbiol Lett"},{"key":"2026032100124908600_bib14","doi-asserted-by":"crossref","first-page":"37260","DOI":"10.1074\/jbc.M202295200","article-title":"Candida albicans phospholipomannan, a new member of the fungal mannose inositol phosphoceramide family","volume":"277","author":"Trinel","year":"2002","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib15","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1086\/375784","article-title":"Candida albicans phospholipomannan is sensed through toll-like receptors","volume":"188","author":"Jouault","year":"2003","journal-title":"J Infect Dis"},{"key":"2026032100124908600_bib16","doi-asserted-by":"crossref","first-page":"D366","DOI":"10.2741\/Yamashita","article-title":"Roles of plasma lipid transfer proteins in reverse cholesterol transport","volume":"6","author":"Yamashita","year":"2001","journal-title":"Front Biosci"},{"key":"2026032100124908600_bib17","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1042\/BST0391033","article-title":"Bioinformatics of the TULIP domain superfamily","volume":"39","author":"Kopec","year":"2011","journal-title":"Biochem Soc Trans"},{"key":"2026032100124908600_bib18","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1006\/bbrc.1997.6970","article-title":"The genomic organization of the genes for human lipopolysaccharide binding protein (LBP) and bactericidal permeability increasing protein (BPI) is highly conserved","volume":"236","author":"Hubacek","year":"1997","journal-title":"Biochem Biophys Res Commun"},{"key":"2026032100124908600_bib19","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1006\/geno.1997.5030","article-title":"Similar organization of the lipopolysaccharide-binding protein (LBP) and phospholipid transfer protein (PLTP) genes suggests a common gene family of lipid-binding proteins","volume":"46","author":"Kirschning","year":"1997","journal-title":"Genomics"},{"key":"2026032100124908600_bib20","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/nchembio.796","article-title":"Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein","volume":"8","author":"Zhang","year":"2012","journal-title":"Nat Chem Biol"},{"key":"2026032100124908600_bib21","doi-asserted-by":"crossref","first-page":"5908","DOI":"10.1074\/jbc.M008420200","article-title":"A hydrophobic cluster at the surface of the human plasma phospholipid transfer protein is critical for activity on high density lipoproteins","volume":"276","author":"Desrumaux","year":"2001","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib22","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S0140-6736(94)91767-1","article-title":"Relative concentrations of endotoxin-binding proteins in body fluids during infection","volume":"344","author":"Opal","year":"1994","journal-title":"Lancet"},{"key":"2026032100124908600_bib23","doi-asserted-by":"crossref","first-page":"3902","DOI":"10.1073\/pnas.052533799","article-title":"Lipid mediator-induced expression of bactericidal\/ permeability-increasing protein (BPI) in human mucosal epithelia","volume":"99","author":"Canny","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100124908600_bib24","doi-asserted-by":"crossref","first-page":"7546","DOI":"10.4049\/jimmunol.180.11.7546","article-title":"Murine bactericidal\/permeability-increasing protein inhibits the endotoxic activity of lipopolysaccharide and gram-negative bacteria","volume":"180","author":"Wittmann","year":"2008","journal-title":"J Immunol"},{"key":"2026032100124908600_bib25","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1161\/01.ATV.14.7.1202","article-title":"Role of the lipopolysaccharide (LPS)-binding protein\/CD14 pathway in LPS induction of tissue factor expression in monocytic cells","volume":"14","author":"Steinemann","year":"1994","journal-title":"Arterioscler Thromb"},{"key":"2026032100124908600_bib26","doi-asserted-by":"crossref","first-page":"3607","DOI":"10.4049\/jimmunol.161.7.3607","article-title":"A synthetic lipopolysaccharide-binding peptide based on amino acids 27-39 of serum amyloid P component inhibits lipopolysaccharide-induced responses in human blood","volume":"161","author":"de Haas","year":"1998","journal-title":"J Immunol"},{"key":"2026032100124908600_bib27","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1172\/JCI2338","article-title":"LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria","volume":"101","author":"Lamping","year":"1998","journal-title":"J Clin Invest"},{"key":"2026032100124908600_bib28","doi-asserted-by":"crossref","first-page":"18702","DOI":"10.1074\/jbc.M802802200","article-title":"Effect of plasma phospholipid transfer protein deficiency on lethal endotoxemia in mice","volume":"283","author":"Gautier","year":"2008","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib29","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1128\/IAI.68.5.2410-2417.2000","article-title":"Lipopolysaccharide-binding protein and phospholipid transfer protein release lipopolysaccharides from gram-negative bacterial membranes","volume":"68","author":"Vesy","year":"2000","journal-title":"Infect Immun"},{"key":"2026032100124908600_bib30","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1194\/jlr.M002295","article-title":"Assessment of cholesteryl ester transfer protein inhibitors for interaction with proteins involved in the immune response to infection","volume":"51","author":"Clark","year":"2010","journal-title":"J Lipid Res"},{"key":"2026032100124908600_bib31","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1097\/SHK.0b013e31816e30fd","article-title":"Human cholesteryl ester transfer protein expression enhances the mouse survival rate in an experimental systemic inflammation model: a novel role for CETP","volume":"30","author":"Cazita","year":"2008","journal-title":"Shock"},{"key":"2026032100124908600_bib32","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1056\/NEJMoa0706628","article-title":"Effects of torcetrapib in patients at high risk for coronary events","volume":"357","author":"Barter","year":"2007","journal-title":"N Engl J Med"},{"key":"2026032100124908600_bib33","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1177\/09680519050110020501","article-title":"Apolipoproteins modulate the inflammatory response to lipopolysaccharide","volume":"11","author":"Berb\u00e9e","year":"2005","journal-title":"J Endotoxin Res"},{"key":"2026032100124908600_bib34","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1128\/IAI.69.5.2821-2828.2001","article-title":"Distribution and kinetics of lipoprotein-bound endotoxin","volume":"69","author":"Levels","year":"2001","journal-title":"Infect Immun"},{"key":"2026032100124908600_bib35","doi-asserted-by":"crossref","first-page":"5140","DOI":"10.1128\/iai.61.12.5140-5146.1993","article-title":"Prevention of endotoxin-induced monokine release by human low- and high-density lipoproteins and by apolipoprotein A-I","volume":"61","author":"Flegel","year":"1993","journal-title":"Infect Immun"},{"key":"2026032100124908600_bib36","doi-asserted-by":"crossref","first-page":"12040","DOI":"10.1073\/pnas.90.24.12040","article-title":"In vivo protection against endotoxin by plasma high density lipoprotein","volume":"90","author":"Levine","year":"1993","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100124908600_bib37","first-page":"548","article-title":"Protective effects of reconstituted high-density lipoprotein in rabbit gram-negative bacteremia models","volume":"126","author":"Hubsch","year":"1995","journal-title":"J Lab Clin Med"},{"key":"2026032100124908600_bib38","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1006\/jsre.1995.1204","article-title":"Reconstituted high-density lipoprotein reduces LPS-stimulated TNF alpha","volume":"59","author":"Casas","year":"1995","journal-title":"J Surg Res"},{"key":"2026032100124908600_bib39","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1084\/jem.184.5.1601","article-title":"Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia","volume":"184","author":"Pajkrt","year":"1996","journal-title":"J Exp Med"},{"key":"2026032100124908600_bib40","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1172\/JCI119427","article-title":"Human recombinant apolipoprotein E redirects lipopolysaccharide from Kupffer cells to liver parenchymal cells in rats In vivo","volume":"99","author":"Rensen","year":"1997","journal-title":"J Clin Invest"},{"key":"2026032100124908600_bib41","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/S0022-2275(20)32147-7","article-title":"Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection","volume":"40","author":"de Bont","year":"1999","journal-title":"J Lipid Res"},{"key":"2026032100124908600_bib42","doi-asserted-by":"crossref","first-page":"8820","DOI":"10.1074\/jbc.M009915200","article-title":"Apolipoprotein E protects against bacterial lipopolysaccharide-induced lethality: a new therapeutic approach to treat gram-negative sepsis","volume":"276","author":"Van Oosten","year":"2001","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib43","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1161\/01.RES.0000187467.67684.43","article-title":"Apolipoprotein E suppresses the type I inflammatory response in vivo","volume":"97","author":"Ali","year":"2005","journal-title":"Circ Res"},{"key":"2026032100124908600_bib44","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1016\/S0022-2275(20)32160-X","article-title":"Apolipoprotein E-deficient mice have impaired innate immune responses to Listeria monocytogenes in vivo","volume":"39","author":"Roselaar","year":"1998","journal-title":"J Lipid Res"},{"key":"2026032100124908600_bib45","doi-asserted-by":"crossref","first-page":"3839","DOI":"10.1074\/jbc.M110.176719","article-title":"The apolipoprotein E-mimetic peptide COG112 inhibits NF-kappaB signaling, proinflammatory cytokine expression, and disease activity in murine models of colitis","volume":"286","author":"Singh","year":"2011","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib46","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1177\/0310057X0903700111","article-title":"APOE genotype affects outcome in a murine model of sepsis: implications for a new treatment strategy","volume":"37","author":"Wang","year":"2009","journal-title":"Anaesth Intensive Care"},{"key":"2026032100124908600_bib47","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.4049\/jimmunol.181.2.1399","article-title":"Apolipoprotein E-mediated immune regulation in sepsis","volume":"181","author":"Kattan","year":"2008","journal-title":"J Immunol"},{"key":"2026032100124908600_bib48","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1172\/JCI116259","article-title":"Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death","volume":"91","author":"Harris","year":"1993","journal-title":"J Clin Invest"},{"key":"2026032100124908600_bib49","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1002\/hep.510270521","article-title":"Chylomicrons alter the hepatic distribution and cellular response to endotoxin in rats","volume":"27","author":"Harris","year":"1998","journal-title":"Hepatology"},{"key":"2026032100124908600_bib50","doi-asserted-by":"crossref","first-page":"258ra143","DOI":"10.1126\/scitranslmed.3008782","article-title":"PCSK9 is a critical regulator of the innate immune response and septic shock outcome","volume":"6","author":"Walley","year":"2014","journal-title":"Sci Transl Med"},{"key":"2026032100124908600_bib51","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1177\/09680519030090060701","article-title":"Hyperlipoproteinemic low-density lipoprotein receptor-deficient mice are more susceptible to sepsis than corresponding wild-type mice","volume":"9","author":"Lanza-Jacoby","year":"2003","journal-title":"J Endotoxin Res"},{"key":"2026032100124908600_bib52","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1172\/JCI118556","article-title":"Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections","volume":"97","author":"Netea","year":"1996","journal-title":"J Clin Invest"},{"key":"2026032100124908600_bib53","doi-asserted-by":"crossref","first-page":"258fs41","DOI":"10.1126\/scitranslmed.3010501","article-title":"Bridging lipid metabolism and innate host defense","volume":"6","author":"dos Santos","year":"2014","journal-title":"Sci Transl Med"},{"key":"2026032100124908600_bib54","doi-asserted-by":"crossref","first-page":"48865","DOI":"10.1074\/jbc.M409699200","article-title":"NARC-1\/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol","volume":"279","author":"Benjannet","year":"2004","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib55","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/nsmb1235","article-title":"Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia","volume":"14","author":"Cunningham","year":"2007","journal-title":"Nat Struct Mol Biol"},{"key":"2026032100124908600_bib56","doi-asserted-by":"crossref","first-page":"43482","DOI":"10.1074\/jbc.M112.380618","article-title":"Furin-cleaved proprotein convertase subtilisin\/kexin type 9 (PCSK9) is active and modulates low density lipoprotein receptor and serum cholesterol levels","volume":"287","author":"Lipari","year":"2012","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib57","doi-asserted-by":"crossref","first-page":"18602","DOI":"10.1074\/jbc.M702027200","article-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","volume":"282","author":"Zhang","year":"2007","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib58","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1194\/jlr.M034371","article-title":"PCSK9-mediated degradation of the LDL receptor generates a 17 kDa C-terminal LDL receptor fragment","volume":"54","author":"Tveten","year":"2013","journal-title":"J Lipid Res"},{"key":"2026032100124908600_bib59","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1056\/NEJMoa1105803","article-title":"Effect of a monoclonal antibody to PCSK9 on LDL cholesterol","volume":"366","author":"Stein","year":"2012","journal-title":"N Engl J Med"},{"key":"2026032100124908600_bib60","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1086\/500615","article-title":"A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol","volume":"78","author":"Kotowski","year":"2006","journal-title":"Am J Hum Genet"},{"key":"2026032100124908600_bib61","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1056\/NEJMoa054013","article-title":"Sequence variations in PCSK9, low LDL, and protection against coronary heart disease","volume":"354","author":"Cohen","year":"2006","journal-title":"N Engl J Med"},{"key":"2026032100124908600_bib62","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1161\/CIRCGENETICS.109.882696","article-title":"Candidate gene association resource (CARe): design, methods, and proof of concept","volume":"3","author":"Musunuru","year":"2010","journal-title":"Circ Cardiovasc Genet"},{"key":"2026032100124908600_bib63","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/ng.327","article-title":"Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants","volume":"41","author":"Kathiresan","year":"2009","journal-title":"Nat Genet"},{"key":"2026032100124908600_bib64","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.tibs.2006.12.008","article-title":"Molecular biology of PCSK9: its role in LDL metabolism","volume":"32","author":"Horton","year":"2007","journal-title":"Trends Biochem Sci"},{"key":"2026032100124908600_bib65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nrcardio.2012.166","article-title":"Lipids. Antibodies against PCSK9: a new era of therapy","volume":"10","author":"King","year":"2013","journal-title":"Nat Rev Cardiol"},{"key":"2026032100124908600_bib66","doi-asserted-by":"crossref","first-page":"28885","DOI":"10.1074\/jbc.M109.052407","article-title":"Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine","volume":"284","author":"Li","year":"2009","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib67","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1074\/jbc.M708098200","article-title":"The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2","volume":"283","author":"Poirier","year":"2008","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib68","doi-asserted-by":"crossref","first-page":"e64145","DOI":"10.1371\/journal.pone.0064145","article-title":"Proprotein convertase subtilisin\/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1)","volume":"8","author":"Canuel","year":"2013","journal-title":"Plos One"},{"key":"2026032100124908600_bib69","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/hep.22911","article-title":"PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression","volume":"50","author":"Labont\u00e9","year":"2009","journal-title":"Hepatology"},{"key":"2026032100124908600_bib70","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.atherosclerosis.2013.03.029","article-title":"Beyond LDL-C lowering: distinct molecular sphingolipids are good indicators of proprotein convertase subtilisin\/kexin type 9 (PCSK9) deficiency","volume":"228","author":"J\u00e4nis","year":"2013","journal-title":"Atherosclerosis"},{"key":"2026032100124908600_bib71","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1161\/CIRCRESAHA.113.302655","article-title":"Loss of plasma proprotein convertase subtilisin\/kexin 9 (PCSK9) after lipoprotein apheresis","volume":"113","author":"Tavori","year":"2013","journal-title":"Circ Res"},{"key":"2026032100124908600_bib72","doi-asserted-by":"crossref","first-page":"8279","DOI":"10.1074\/jbc.M112.421370","article-title":"Low density lipoprotein binds to proprotein convertase subtilisin\/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation","volume":"288","author":"Kosenko","year":"2013","journal-title":"J Biol Chem"},{"key":"2026032100124908600_bib73","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.trsl.2012.01.010","article-title":"Serum levels of proprotein convertase subtilisin\/kexin type 9 in subjects with familial hypercholesterolemia indicate that proprotein convertase subtilisin\/kexin type 9 is cleared from plasma by low-density lipoprotein receptor-independent pathways","volume":"160","author":"Cameron","year":"2012","journal-title":"Transl Res"},{"key":"2026032100124908600_bib74","doi-asserted-by":"crossref","first-page":"e1002967","DOI":"10.1371\/journal.ppat.1002967","article-title":"Scavenger receptor class a plays a central role in mediating mortality and the development of the pro-inflammatory phenotype in polymicrobial sepsis","volume":"8","author":"Ozment","year":"2012","journal-title":"Plos Pathog"},{"key":"2026032100124908600_bib75","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.jaci.2014.01.032","article-title":"APO\u03b54 is associated with enhanced in vivo innate immune responses in human subjects","volume":"134","author":"Gale","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100124908600_bib76","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/1476-511X-13-79","article-title":"Haplotype analysis of ApoAI gene and sepsis-associated acute lung injury","volume":"13","author":"Hao","year":"2014","journal-title":"Lipids Health Dis"},{"key":"2026032100124908600_bib77","doi-asserted-by":"crossref","first-page":"E732","DOI":"10.1210\/jc.2012-4236","article-title":"Plasma PCSK9 is a late biomarker of severity in patients with severe trauma injury","volume":"98","author":"Le Bras","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"2026032100124908600_bib78","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1194\/jlr.P023994","article-title":"Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia","volume":"53","author":"Huijgen","year":"2012","journal-title":"J Lipid Res"},{"key":"2026032100124908600_bib79","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1042\/CS20110129","article-title":"Plasma proprotein convertase subtilisin kexin type 9 is a heritable trait of familial combined hyperlipidaemia","volume":"121","author":"Brouwers","year":"2011","journal-title":"Clin Sci (Lond)"},{"key":"2026032100124908600_bib80","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.numecd.2012.11.008","article-title":"Plasma proprotein convertase subtilisin kexin type 9 levels are related to markers of cholesterol synthesis in familial combined hyperlipidemia","volume":"23","author":"Brouwers","year":"2013","journal-title":"Nutr Metab Cardiovasc Dis"},{"key":"2026032100124908600_bib81","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.atherosclerosis.2014.04.001","article-title":"Association of plasma PCSK9 levels with white blood cell count and its subsets in patients with stable coronary artery disease","volume":"234","author":"Li","year":"2014","journal-title":"Atherosclerosis"},{"key":"2026032100124908600_bib82","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.jacl.2014.07.001","article-title":"Relation of circulating PCSK9 concentration to fibrinogen in patients with stable coronary artery disease","volume":"8","author":"Zhang","year":"2014","journal-title":"J Clin Lipidol"},{"key":"2026032100124908600_bib83","doi-asserted-by":"crossref","first-page":"e106294","DOI":"10.1371\/journal.pone.0106294","article-title":"Plasma PCSK9 levels are elevated with acute myocardial infarction in two independent retrospective angiographic studies","volume":"9","author":"Almontashiri","year":"2014","journal-title":"Plos One"},{"key":"2026032100124908600_bib84","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1161\/ATVBAHA.111.242461","article-title":"Endogenous estrogens lower plasma PCSK9 and LDL cholesterol but not Lp(a) or bile acid synthesis in women","volume":"32","author":"Persson","year":"2012","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026032100124908600_bib85","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.clinbiochem.2014.03.022","article-title":"The effect of insulin on circulating PCSK9 in postmenopausal obese women","volume":"47","author":"Awan","year":"2014","journal-title":"Clin Biochem"},{"key":"2026032100124908600_bib86","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1756-6614-7-4","article-title":"Acute TSH stimulation in vivo does not alter serum PCSK9 levels","volume":"7","author":"Gagnon","year":"2014","journal-title":"Thyroid Res"},{"key":"2026032100124908600_bib87","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1194\/jlr.M051664","article-title":"Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans","volume":"55","author":"Bonde","year":"2014","journal-title":"J Lipid Res"},{"key":"2026032100124908600_bib88","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.atherosclerosis.2011.07.098","article-title":"Lack of association between plasma PCSK9 and LDL-apoB100 catabolism in patients with uncontrolled type 2 diabetes","volume":"219","author":"Verg\u00e8s","year":"2011","journal-title":"Atherosclerosis"},{"key":"2026032100124908600_bib89","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1515\/CCLM.1999.059","article-title":"Reduction of circulating cholesterol and apolipoprotein levels during sepsis","volume":"37","author":"Fraunberger","year":"1999","journal-title":"Clin Chem Lab Med"},{"key":"2026032100124908600_bib90","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00726-004-0064-x","article-title":"The relationship between plasma cholesterol, amino acids and acute phase proteins in sepsis","volume":"27","author":"Chiarla","year":"2004","journal-title":"Amino Acids"},{"key":"2026032100124908600_bib91","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1097\/01.CCM.0000171183.79525.6B","article-title":"Low serum level of high-density lipoprotein cholesterol is a poor prognostic factor for severe sepsis","volume":"33","author":"Chien","year":"2005","journal-title":"Crit Care Med"},{"key":"2026032100124908600_bib92","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.jclinane.2006.10.008","article-title":"High C-reactive protein and low cholesterol levels are prognostic markers of survival in severe sepsis","volume":"19","author":"Memi\u015f","year":"2007","journal-title":"J Clin Anesth"},{"key":"2026032100124908600_bib93","first-page":"343","article-title":"Low serum LDL cholesterol levels and the risk of fever, sepsis, and malignancy","volume":"37","author":"Shor","year":"2007","journal-title":"Ann Clin Lab Sci"},{"key":"2026032100124908600_bib94","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1097\/CCM.0000000000000165","article-title":"Low preoperative cholesterol level is a risk factor of sepsis and poor clinical outcome in patients undergoing cardiac surgery with cardiopulmonary bypass","volume":"42","author":"Lagrost","year":"2014","journal-title":"Crit Care Med"},{"key":"2026032100124908600_bib95","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.clinbiochem.2014.03.008","article-title":"Plasma proprotein convertase subtilisin-kexin type 9 is predominantly related to intermediate density lipoproteins","volume":"47","author":"Kwakernaak","year":"2014","journal-title":"Clin Biochem"},{"key":"2026032100124908600_bib96","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1210\/jc.2009-0141","article-title":"Genetic and metabolic determinants of plasma PCSK9 levels","volume":"94","author":"Lakoski","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"2026032100124908600_bib97","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1373\/clinchem.2007.099747","article-title":"Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment","volume":"54","author":"Lambert","year":"2008","journal-title":"Clin Chem"},{"key":"2026032100124908600_bib98","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1373\/clinchem.2009.128645","article-title":"Plasma proprotein convertase subtilisin\/kexin type 9: a marker of LDL apolipoprotein B-100 catabolism?","volume":"55","author":"Chan","year":"2009","journal-title":"Clin Chem"},{"key":"2026032100124908600_bib99","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1743-7075-10-4","article-title":"Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets","volume":"10","author":"Cariou","year":"2013","journal-title":"Nutr Metab (Lond)"},{"key":"2026032100124908600_bib100","doi-asserted-by":"crossref","first-page":"3359","DOI":"10.1194\/jlr.P009860","article-title":"Fasting reduces plasma proprotein convertase, subtilisin\/kexin type 9 and cholesterol biosynthesis in humans","volume":"51","author":"Browning","year":"2010","journal-title":"J Lipid Res"},{"key":"2026032100124908600_bib101","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.atherosclerosis.2010.04.015","article-title":"Association between plasma PCSK9 and gamma-glutamyl transferase levels in diabetic patients","volume":"211","author":"Cariou","year":"2010","journal-title":"Atherosclerosis"},{"key":"2026032100124908600_bib102","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.atherosclerosis.2011.03.023","article-title":"Plasma proprotein convertase subtilisin kexin type 9 is not altered in subjects with impaired glucose metabolism and type 2 diabetes mellitus, but its relationship with non-HDL cholesterol and apolipoprotein B may be modified by type 2 diabetes mellitus: the CODAM study","volume":"217","author":"Brouwers","year":"2011","journal-title":"Atherosclerosis"},{"key":"2026032100124908600_bib103","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.atherosclerosis.2010.10.028","article-title":"Plasma proprotein convertase subtilisin-kexin type 9 does not change during 24h insulin infusion in healthy subjects and type 2 diabetic patients","volume":"214","author":"Kappelle","year":"2011","journal-title":"Atherosclerosis"},{"key":"2026032100124908600_bib104","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1053\/j.ajkd.2013.10.042","article-title":"Plasma PCSK9 in nephrotic syndrome and in peritoneal dialysis: a cross-sectional study","volume":"63","author":"Jin","year":"2014","journal-title":"Am J Kidney Dis"},{"key":"2026032100124908600_bib105","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1093\/ndt\/gft439","article-title":"Role of PCSK9 and IDOL in the pathogenesis of acquired LDL receptor deficiency and hypercholesterolemia in nephrotic syndrome","volume":"29","author":"Liu","year":"2014","journal-title":"Nephrol Dial Transplant"},{"key":"2026032100124908600_bib106","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/1476-511X-12-70","article-title":"Differential effects of PCSK9 loss of function variants on serum lipid and PCSK9 levels in Caucasian and African Canadian populations","volume":"12","author":"Mayne","year":"2013","journal-title":"Lipids Health Dis"},{"key":"2026032100124908600_bib107","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1161\/01.ATV.0000134621.14315.43","article-title":"Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia","volume":"24","author":"Dubuc","year":"2004","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026032100124908600_bib108","doi-asserted-by":"crossref","first-page":"5374","DOI":"10.1073\/pnas.0501652102","article-title":"Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9","volume":"102","author":"Rashid","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100124908600_bib109","first-page":"163","article-title":"Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels","volume":"120","author":"Davignon","year":"2009","journal-title":"Trans Am Clin Climatol Assoc"},{"key":"2026032100124908600_bib110","doi-asserted-by":"crossref","first-page":"2714","DOI":"10.1194\/jlr.M008144","article-title":"High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol","volume":"51","author":"Welder","year":"2010","journal-title":"J Lipid Res"},{"key":"2026032100124908600_bib111","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.atherosclerosis.2010.05.027","article-title":"Plasma PCSK9 is increased by fenofibrate and atorvastatin in a non-additive fashion in diabetic patients","volume":"212","author":"Costet","year":"2010","journal-title":"Atherosclerosis"},{"key":"2026032100124908600_bib112","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1476-511X-10-38","article-title":"Effects of currently prescribed LDL-C-lowering drugs on PCSK9 and implications for the next generation of LDL-C-lowering agents","volume":"10","author":"Konrad","year":"2011","journal-title":"Lipids Health Dis"},{"key":"2026032100124908600_bib113","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.atherosclerosis.2012.07.036","article-title":"Long-term effects of ezetimibe-plus-statin therapy on low-density lipoprotein cholesterol levels as compared with double-dose statin therapy in patients with coronary artery disease","volume":"224","author":"Okada","year":"2012","journal-title":"Atherosclerosis"},{"key":"2026032100124908600_bib114","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1373\/clinchem.2011.172932","article-title":"Rosuvastatin, proprotein convertase subtilisin\/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial","volume":"58","author":"Awan","year":"2012","journal-title":"Clin Chem"},{"key":"2026032100124908600_bib115","doi-asserted-by":"crossref","first-page":"e60095","DOI":"10.1371\/journal.pone.0060095","article-title":"Evidence from a randomized trial that simvastatin, but not ezetimibe, upregulates circulating PCSK9 levels","volume":"8","author":"Berthold","year":"2013","journal-title":"Plos One"},{"key":"2026032100124908600_bib116","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.jacl.2014.02.008","article-title":"Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects","volume":"8","author":"Anderson","year":"2014","journal-title":"J Clin Lipidol"},{"key":"2026032100124908600_bib117","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.amjcard.2009.08.651","article-title":"Meta-analysis of comparative efficacy of increasing dose of Atorvastatin versus Rosuvastatin versus Simvastatin on lowering levels of atherogenic lipids (from VOYAGER)","volume":"105","author":"Nicholls","year":"2010","journal-title":"Am J Cardiol"},{"key":"2026032100124908600_bib118","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1194\/jlr.M013664","article-title":"Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9","volume":"52","author":"Ason","year":"2011","journal-title":"J Lipid Res"},{"key":"2026032100124908600_bib119","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.bbrc.2007.03.196","article-title":"Bile acids and lipoprotein metabolism: effects of cholestyramine and chenodeoxycholic acid on human hepatic mRNA expression","volume":"357","author":"Nilsson","year":"2007","journal-title":"Biochem Biophys Res Commun"},{"key":"2026032100124908600_bib120","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.atherosclerosis.2011.02.012","article-title":"Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin\/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: results from a crossover study","volume":"217","author":"Noguchi","year":"2011","journal-title":"Atherosclerosis"},{"key":"2026032100124908600_bib121","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.amjcard.2014.10.018","article-title":"Effects of niacin, statin, and fenofibrate on circulating proprotein convertase subtilisin\/kexin type 9 levels in patients with dyslipidemia","volume":"115","author":"Khera","year":"2015","journal-title":"Am J Cardiol"},{"key":"2026032100124908600_bib122","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1111\/j.1463-1326.2010.01229.x","article-title":"Fenofibrate concomitantly decreases serum proprotein convertase subtilisin\/kexin type 9 and very-low-density lipoprotein particle concentrations in statin-treated type 2 diabetic patients","volume":"12","author":"Chan","year":"2010","journal-title":"Diabetes Obes Metab"},{"key":"2026032100124908600_bib123","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1073\/pnas.78.2.1194","article-title":"Regulatory role for hepatic low density lipoprotein receptors in vivo in the dog","volume":"78","author":"Kovanen","year":"1981","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100124908600_bib124","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/j.1440-1681.2009.05337.x","article-title":"Atorvastatin increases expression of low-density lipoprotein receptor mRNA in human circulating mononuclear cells","volume":"37","author":"Pocathikorn","year":"2010","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"2026032100124908600_bib125","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1172\/JCI39843","article-title":"Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease","volume":"120","author":"Rosch","year":"2010","journal-title":"J Clin Invest"},{"key":"2026032100124908600_bib126","doi-asserted-by":"crossref","first-page":"H866","DOI":"10.1152\/ajpheart.01232.2008","article-title":"Apolipoprotein A-I mimetic peptide treatment inhibits inflammatory responses and improves survival in septic rats","volume":"297","author":"Zhang","year":"2009","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2026032100124908600_bib127","doi-asserted-by":"crossref","first-page":"E367","DOI":"10.1503\/cmaj.111017","article-title":"The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial","volume":"184","author":"Novack","year":"2012","journal-title":"CMAJ"},{"key":"2026032100124908600_bib128","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1007\/s11606-011-1826-2","article-title":"Association between statins given in hospital and mortality in pneumonia patients","volume":"27","author":"Rothberg","year":"2012","journal-title":"J Gen Intern Med"},{"key":"2026032100124908600_bib129","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1164\/rccm.201006-0955OC","article-title":"Continuation of statin therapy in patients with presumed infection: a randomized controlled trial","volume":"183","author":"Kruger","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100124908600_bib130","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1056\/NEJMoa1401520","article-title":"Rosuvastatin for sepsis-associated acute respiratory distress syndrome","volume":"370","author":"Truwit","year":"2014","journal-title":"N Engl J Med"},{"key":"2026032100124908600_bib131","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1001\/jama.2013.280031","article-title":"Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial","volume":"310","author":"Papazian","year":"2013","journal-title":"JAMA"},{"key":"2026032100124908600_bib132","doi-asserted-by":"crossref","first-page":"8370","DOI":"10.1073\/pnas.83.21.8370","article-title":"Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits","volume":"83","author":"Ma","year":"1986","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100124908600_bib133","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0005-2760(91)90215-4","article-title":"Regulation of the uptake of high-density lipoprotein-originated cholesteryl ester by HepG2 cells: role of low-density lipoprotein and plasma lipid transfer protein","volume":"1084","author":"Francis","year":"1991","journal-title":"Biochim Biophys Acta"},{"key":"2026032100124908600_bib134","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1056\/NEJMoa1206797","article-title":"Effects of dalcetrapib in patients with a recent acute coronary syndrome","volume":"367","author":"Schwartz","year":"2012","journal-title":"N Engl J Med"},{"key":"2026032100124908600_bib135","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1161\/ATVBAHA.110.207142","article-title":"Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib","volume":"30","author":"Yvan-Charvet","year":"2010","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026032100124908600_bib136","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1159\/000315916","article-title":"Rationale of extracorporeal removal of endotoxin in sepsis: theory, timing and technique","volume":"167","author":"Ronco","year":"2010","journal-title":"Contrib Nephrol"},{"key":"2026032100124908600_bib137","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1097\/SHK.0b013e318225f839","article-title":"Polymyxin B-immobilized fiber column hemoperfusion therapy for septic shock","volume":"36","author":"Mitaka","year":"2011","journal-title":"Shock"},{"key":"2026032100124908600_bib138","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1001\/jama.2009.856","article-title":"Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial","volume":"301","author":"Cruz","year":"2009","journal-title":"JAMA"},{"key":"2026032100124908600_bib139","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/1745-6215-15-218","article-title":"The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial","volume":"15","author":"Klein","year":"2014","journal-title":"Trials"},{"key":"2026032100124908600_bib140","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.jacc.2012.08.986","article-title":"Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins","volume":"60","author":"Dias","year":"2012","journal-title":"J Am Coll Cardiol"},{"key":"2026032100124908600_bib141","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1124\/jpet.114.214221","article-title":"Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering","volume":"350","author":"Mitchell","year":"2014","journal-title":"J Pharmacol Exp Ther"},{"key":"2026032100124908600_bib142","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S0140-6736(13)61914-5","article-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","volume":"383","author":"Fitzgerald","year":"2014","journal-title":"Lancet"},{"key":"2026032100124908600_bib143","doi-asserted-by":"crossref","first-page":"11915","DOI":"10.1073\/pnas.0805434105","article-title":"Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates","volume":"105","author":"Frank-Kamenetsky","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100124908600_bib144","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1056\/NEJMoa1201832","article-title":"Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia","volume":"367","author":"Roth","year":"2012","journal-title":"N Engl J Med"},{"key":"2026032100124908600_bib145","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1056\/NEJMoa1316222","article-title":"A 52-week placebo-controlled trial of evolocumab in hyperlipidemia","volume":"370","author":"Blom","year":"2014","journal-title":"N Engl J Med"},{"key":"2026032100124908600_bib146","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1161\/CIRCULATIONAHA.112.144055","article-title":"Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin\/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial","volume":"126","author":"Raal","year":"2012","journal-title":"Circulation"},{"key":"2026032100124908600_bib147","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0140-6736(12)60771-5","article-title":"Effect of a monoclonal antibody to PCSK9, REGN727\/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial","volume":"380","author":"Stein","year":"2012","journal-title":"Lancet"},{"key":"2026032100124908600_bib148","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1001\/jama.2012.25790","article-title":"Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial","volume":"308","author":"Sullivan","year":"2012","journal-title":"JAMA"},{"key":"2026032100124908600_bib149","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1097\/MOL.0000000000000021","article-title":"Low-density lipoprotein cholesterol reduction by inhibition of PCSK9","volume":"24","author":"Stein","year":"2013","journal-title":"Curr Opin Lipidol"},{"key":"2026032100124908600_bib150","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/j.jacc.2014.01.006","article-title":"Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials","volume":"63","author":"Raal","year":"2014","journal-title":"J Am Coll Cardiol"},{"key":"2026032100124908600_bib151","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0140-6736(14)61374-X","article-title":"TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial","volume":"385","author":"Raal","year":"2015","journal-title":"Lancet"},{"key":"2026032100124908600_bib152","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0140-6736(14)61399-4","article-title":"RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial","volume":"385","author":"Raal","year":"2015","journal-title":"Lancet"},{"key":"2026032100124908600_bib153","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1093\/eurheartj\/ehu085","article-title":"Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials","volume":"35","author":"Stein","year":"2014","journal-title":"Eur Heart J"},{"key":"2026032100124908600_bib154","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1146\/annurev-med-022613-090402","article-title":"Reduction of low-density lipoprotein cholesterol by monoclonal antibody inhibition of PCSK9","volume":"65","author":"Stein","year":"2014","journal-title":"Annu Rev Med"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/192\/11\/1275\/67231085\/ajrccm_192_11_1275.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/192\/11\/1275\/67231085\/ajrccm_192_11_1275.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T04:13:18Z","timestamp":1774066398000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/192\/11\/1275\/8504761"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,1]]},"references-count":154,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2015,12,1]]},"published-print":{"date-parts":[[2015,12,1]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201505-0876ci","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,12]]},"published":{"date-parts":[[2015,12,1]]}}}