{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T18:21:24Z","timestamp":1793298084476,"version":"4.5.0"},"reference-count":184,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:00:00Z","timestamp":1722297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Proprotein convertase subtilisin\/kexin type 9 (PCSK9) is primarily secreted by hepatocytes. PCSK9 is critical in liver low-density lipoprotein receptors (LDLRs) metabolism. In addition to its hepatocellular presence, PCSK9 has also been detected in cardiac, cerebral, islet, renal, adipose, and other tissues. Once perceived primarily as a \u201charmful factor,\u201d PCSK9 has been a focal point for the targeted inhibition of both systemic circulation and localized tissues to treat diseases. However, PCSK9 also contributes to the maintenance of normal physiological functions in numerous extrahepatic tissues, encompassing both LDLR-dependent and -independent pathways. Consequently, PCSK9 deficiency may harm extrahepatic tissues in close association with several pathophysiological processes, such as lipid accumulation, mitochondrial impairment, insulin resistance, and abnormal neural differentiation. This review encapsulates the beneficial effects of PCSK9 on the physiological processes and potential disorders arising from PCSK9 deficiency in extrahepatic tissues. This review also provides a comprehensive analysis of the disparities between experimental and clinical research findings regarding the potential harm associated with PCSK9 deficiency. The aim is to improve the current understanding of the diverse effects of PCSK9 inhibition.<\/jats:p>","DOI":"10.3389\/fphar.2024.1413123","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T04:50:19Z","timestamp":1722315019000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Proprotein convertase subtilisin\/kexin type 9 deficiency in extrahepatic tissues: emerging considerations"],"prefix":"10.3389","volume":"15","author":[{"given":"Fengyuan","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"En","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S17","DOI":"10.2337\/dc22-S002","article-title":"2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2022","volume":"45","year":"2022","journal-title":"Diabetes Care"},{"key":"B2","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/ng1161","article-title":"Mutations in PCSK9 cause autosomal dominant hypercholesterolemia","volume":"34","author":"Abifadel","year":"2003","journal-title":"Nat. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"119310","DOI":"10.1016\/j.lfs.2021.119310","article-title":"HMGB1\/RAGE\/TLR4 axis and glutamate as novel targets for PCSK9 inhibitor in high fat cholesterol diet induced cognitive impairment and amyloidosis","volume":"273","author":"Abuelezz","year":"2021","journal-title":"Life Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"17559","DOI":"10.1038\/srep17559","article-title":"Identification of PCSK9 as a novel serum biomarker for the prenatal diagnosis of neural tube defects using iTRAQ quantitative proteomics","volume":"5","author":"An","year":"2015","journal-title":"Sci. Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"107250","DOI":"10.1016\/j.envint.2022.107250","article-title":"G protein-coupled estrogen receptor activation by bisphenol-A disrupts the protection from apoptosis conferred by the estrogen receptors ER\u03b1 and ER\u03b2 in pancreatic beta cells","volume":"164","author":"Babiloni-Chust","year":"2022","journal-title":"Environ. Int."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1177\/2047487317724342","article-title":"PCSK9 deficiency results in increased ectopic fat accumulation in experimental models and in humans","volume":"24","author":"Baragetti","year":"2017","journal-title":"Eur. J. Prev. Cardiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"9884","DOI":"10.3390\/ijms22189884","article-title":"Renal ischemia\/reperfusion early induces myostatin and PCSK9 expression in rat kidneys and HK-2 cells","volume":"22","author":"Barisione","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.atherosclerosis.2015.01.012","article-title":"PCSK9-deficiency does not alter blood pressure and sodium balance in mouse models of hypertension","volume":"239","author":"Berger","year":"2015","journal-title":"Atherosclerosis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"3577","DOI":"10.1210\/jc.2008-0269","article-title":"A new PCSK9 gene promoter variant affects gene expression and causes autosomal dominant hypercholesterolemia","volume":"93","author":"Blesa","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1466","DOI":"10.1111\/j.1600-0854.2012.01407.x","article-title":"Cholesterol accumulation increases insulin granule size and impairs membrane trafficking","volume":"13","author":"Bogan","year":"2012","journal-title":"Traffic"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2051","DOI":"10.1007\/s00125-015-3659-8","article-title":"The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis","volume":"58","author":"Bonnefond","year":"2015","journal-title":"Diabetologia"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1046\/j.1523-1755.2000.00968.x","article-title":"Dysfunction of epithelial sodium transport: from human to mouse","volume":"57","author":"Bonny","year":"2000","journal-title":"Kidney Int."},{"key":"B13","doi-asserted-by":"publisher","first-page":"245","DOI":"10.3390\/ijms20020245","article-title":"PCSK9 is expressed in human visceral adipose tissue and regulated by insulin and cardiac natriuretic peptides","volume":"20","author":"Bordicchia","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1074\/jbc.M808363200","article-title":"Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants","volume":"284","author":"Bottomley","year":"2009","journal-title":"J. Biol. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"155627","DOI":"10.1016\/j.metabol.2023.155627","article-title":"The key role of inflammation in the pathogenesis and management of obesity and CVD","volume":"145","author":"Boutari","year":"2023","journal-title":"Metabolism"},{"key":"B16","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/nm1546","article-title":"Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment","volume":"13","author":"Brunham","year":"2007","journal-title":"Nat. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.diabet.2017.07.009","article-title":"Circulating PCSK9 levels in acute coronary syndrome: results from the PC-SCA-9 prospective study","volume":"43","author":"Cariou","year":"2017","journal-title":"Diabetes Metab."},{"key":"B18","doi-asserted-by":"publisher","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":"B19","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1161\/ATVBAHA.109.194191","article-title":"PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia","volume":"29","author":"Cariou","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1007\/s11883-022-01074-y","article-title":"PCSK9 inhibition and risk of diabetes: should we worry?","volume":"24","author":"Carugo","year":"2022","journal-title":"Curr. Atheroscler. Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1146\/annurev.cellbio.22.010305.104656","article-title":"Cholesterol sensing, trafficking, and esterification","volume":"22","author":"Chang","year":"2006","journal-title":"Annu. Rev. Cell. Dev. Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1007\/s11745-014-3895-6","article-title":"PCSK9 is present in human cerebrospinal fluid and is maintained at remarkably constant concentrations throughout the course of the day","volume":"49","author":"Chen","year":"2014","journal-title":"Lipids"},{"key":"B23","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1161\/CIRCULATIONAHA.121.054768","article-title":"PTPMT1 is required for embryonic cardiac cardiolipin biosynthesis to regulate mitochondrial morphogenesis and heart development","volume":"144","author":"Chen","year":"2021","journal-title":"Circulation"},{"key":"B24","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.atherosclerosis.2016.03.010","article-title":"PCSK9 in relation to coronary plaque inflammation: results of the ATHEROREMO-IVUS study","volume":"248","author":"Cheng","year":"2016","journal-title":"Atherosclerosis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"100186","DOI":"10.1016\/j.jcte.2019.100186","article-title":"C679X loss-of-function PCSK9 variant is associated with lower fasting glucose in black South African adolescents: birth to Twenty Plus Cohort","volume":"16","author":"Chikowore","year":"2019","journal-title":"J. Clin. Transl. Endocrinol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1016\/j.bbagen.2012.04.001","article-title":"CD36 promotes adipocyte differentiation and adipogenesis","volume":"1820","author":"Christiaens","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"B27","doi-asserted-by":"publisher","first-page":"3449","DOI":"10.1210\/en.2002-220273","article-title":"Low density lipoprotein can cause death of islet beta-cells by its cellular uptake and oxidative modification","volume":"143","author":"Cnop","year":"2002","journal-title":"Endocrinology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"6211","DOI":"10.1074\/jbc.M508582200","article-title":"Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c","volume":"281","author":"Costet","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1186\/s12967-020-02362-4","article-title":"Beneficial impact of epigallocatechingallate on LDL-C through PCSK9\/LDLR pathway by blocking HNF1\u03b1 and activating FoxO3a","volume":"18","author":"Cui","year":"2020","journal-title":"J. Transl. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.cca.2014.10.044","article-title":"PCSK9 and its modulation","volume":"440","author":"Cui","year":"2015","journal-title":"Clin. Chim. Acta"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e14721","DOI":"10.14814\/phy2.14721","article-title":"Lower plasma PCSK9 in normocholesterolemic subjects is associated with upregulated adipose tissue surface-expression of LDLR and CD36 and NLRP3 inflammasome","volume":"9","author":"Cyr","year":"2021","journal-title":"Physiol. Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3078","DOI":"10.1093\/eurheartj\/ehab431","article-title":"PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction","volume":"42","author":"Da Dalt","year":"2021","journal-title":"Eur. Heart J."},{"key":"B33","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1093\/eurheartj\/ehy357","article-title":"PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor","volume":"40","author":"Da Dalt","year":"2019","journal-title":"Eur. Heart J."},{"key":"B34","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":"B35","doi-asserted-by":"publisher","first-page":"2517","DOI":"10.1161\/ATVBAHA.115.306032","article-title":"PCSK9 induces CD36 degradation and affects long-chain fatty acid uptake and triglyceride metabolism in adipocytes and in mouse liver","volume":"35","author":"Demers","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1172\/JCI81542","article-title":"E2F1 mediates sustained lipogenesis and contributes to hepatic steatosis","volume":"126","author":"Denechaud","year":"2016","journal-title":"J. Clin. Investig."},{"key":"B37","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1007\/s11745-015-4020-1","article-title":"Acute intake of plant stanol esters induces changes in lipid and lipoprotein metabolism-related gene expression in the liver and intestines of mice","volume":"50","author":"De Smet","year":"2015","journal-title":"Lipids"},{"key":"B38","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/s11010-018-3484-8","article-title":"Up-regulation of PCSK9 gene expression and diminished level of LDL-receptor in rat liver as a potential cause of post-lipectomy hypercholesterolemia","volume":"455","author":"Dettlaff-Pokora","year":"2019","journal-title":"Mol. Cell. Biochem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1093\/cvr\/cvz313","article-title":"PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1","volume":"116","author":"Ding","year":"2020","journal-title":"Cardiovasc Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1093\/cvr\/cvy128","article-title":"PCSK9 expression in the ischaemic heart and its relationship to infarct size, cardiac function, and development of autophagy","volume":"114","author":"Ding","year":"2018","journal-title":"Cardiovasc Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1348913","DOI":"10.1155\/2020\/1348913","article-title":"PCSK9 expression in epicardial adipose tissue: molecular association with local tissue inflammation","volume":"2020","author":"Dozio","year":"2020","journal-title":"Mediat. Inflamm."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1016\/j.bbalip.2016.02.016","article-title":"Lipid metabolism and signaling in cardiac lipotoxicity","volume":"1861","author":"DSouza","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"B43","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1007\/s00592-016-0936-z","article-title":"Retrograde cholesterol transport in the human Caco-2\/TC7 cell line: a model to study trans-intestinal cholesterol excretion in atherogenic and diabetic dyslipidemia","volume":"54","author":"Dugardin","year":"2017","journal-title":"Acta Diabetol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.biochi.2004.09.018","article-title":"SREBP transcription factors: master regulators of lipid homeostasis","volume":"86","author":"Eberl\u00e9","year":"2004","journal-title":"Biochimie"},{"key":"B45","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/s41574-020-0355-7","article-title":"Pancreatic \u03b2-cells in type 1 and type 2 diabetes mellitus: different pathways to failure","volume":"16","author":"Eizirik","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1016\/j.echo.2010.09.007","article-title":"Impaired myocardial radial function in asymptomatic patients with type 2 diabetes mellitus: a speckle-tracking imaging study","volume":"23","author":"Ernande","year":"2010","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"B47","doi-asserted-by":"publisher","first-page":"309","DOI":"10.4149\/gpb_2017047","article-title":"Exercise training increased gene expression of LDL-R and PCSK9 in intestine: link to transintestinal cholesterol excretion","volume":"37","author":"Farahnak","year":"2018","journal-title":"Gen. Physiol. Biophys."},{"key":"B48","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.atherosclerosis.2018.08.036","article-title":"Long-term safety and efficacy of alirocumab in patients with heterozygous familial hypercholesterolemia: an open-label extension of the ODYSSEY program","volume":"278","author":"Farnier","year":"2018","journal-title":"Atherosclerosis"},{"key":"B49","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.1056\/NEJMoa1604304","article-title":"Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes","volume":"375","author":"Ference","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e014758","DOI":"10.1161\/JAHA.119.014758","article-title":"PCSK9 protein and rs562556 polymorphism are associated with arterial plaques in healthy middle-aged population: the STANISLAS cohort","volume":"9","author":"Ferreira","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"B51","doi-asserted-by":"publisher","first-page":"106439","DOI":"10.1016\/j.phrs.2022.106439","article-title":"Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9","volume":"184","author":"Ferri","year":"2022","journal-title":"Pharmacol. Res."},{"key":"B52","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1111\/dom.13380","article-title":"Pancreatic islet of Langerhans' cytoarchitecture and ultrastructure in normal glucose tolerance and in type 2 diabetes mellitus","volume":"20","author":"Folli","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"B53","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1016\/j.bbalip.2017.05.002","article-title":"APP, APLP2 and LRP1 interact with PCSK9 but are not required for PCSK9-mediated degradation of the LDLR in vivo","volume":"1862","author":"Fu","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Cell. Biol. Lipids"},{"key":"B54","doi-asserted-by":"publisher","first-page":"e011382","DOI":"10.1161\/CIRCINTERVENTIONS.121.011382","article-title":"Effect of evolocumab in patients with prior percutaneous coronary intervention","volume":"15","author":"Furtado","year":"2022","journal-title":"Circ. Cardiovasc Interv."},{"key":"B55","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1210\/jc.2004-1027","article-title":"Liddle's syndrome caused by a novel mutation in the proline-rich PY motif of the epithelial sodium channel beta-subunit","volume":"90","author":"Furuhashi","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B56","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/s11883-022-00995-y","article-title":"Transintestinal cholesterol excretion in health and disease","volume":"24","author":"Gar\u00e7on","year":"2022","journal-title":"Curr. Atheroscler. Rep."},{"key":"B57","doi-asserted-by":"publisher","first-page":"251","DOI":"10.2337\/dc21-0955","article-title":"Effect of loss-of-function genetic variants in PCSK9 on glycemic traits, neurocognitive impairment, and hepatobiliary function","volume":"45","author":"Ghouse","year":"2022","journal-title":"Diabetes Care"},{"key":"B58","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1002\/jcph.840","article-title":"Impact of target-mediated elimination on the dose and regimen of evolocumab, a human monoclonal antibody against proprotein convertase subtilisin\/kexin type 9 (PCSK9)","volume":"57","author":"Gibbs","year":"2017","journal-title":"J. Clin. Pharmacol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1016\/j.cmet.2012.04.006","article-title":"Lipid metabolism and toxicity in the heart","volume":"15","author":"Goldberg","year":"2012","journal-title":"Cell. Metab."},{"key":"B60","doi-asserted-by":"publisher","first-page":"14076","DOI":"10.1038\/srep14076","article-title":"Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis","volume":"5","author":"Gotoh","year":"2015","journal-title":"Sci. Rep."},{"key":"B61","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1530\/REP-21-0164","article-title":"Contribution of high-fat diet-induced PCSK9 upregulation to a mouse model of PCOS is mediated partly by SREBP2","volume":"162","author":"Guo","year":"","journal-title":"Reproduction"},{"key":"B62","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.1002\/jcp.30025","article-title":"Physiology and role of PCSK9 in vascular disease: potential impact of localized PCSK9 in vascular wall","volume":"236","author":"Guo","year":"","journal-title":"J. Cell. Physiol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1007\/s00418-016-1535-3","article-title":"Expression of epithelial sodium channel (ENaC) and CFTR in the human epidermis and epidermal appendages","volume":"147","author":"Hanukoglu","year":"2017","journal-title":"Histochem Cell. Biol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1536\/ihj.22-052","article-title":"Effect of the early application of evolocumab on blood lipid profile and cardiovascular prognosis in patients with extremely high-risk acute coronary syndrome","volume":"63","author":"Hao","year":"2022","journal-title":"Int. Heart J."},{"key":"B65","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1038\/s41431-022-01107-9","article-title":"Genetic analysis of the PCSK9 locus in psychological, psychiatric, metabolic and cardiovascular traits in UK Biobank","volume":"30","author":"Hay","year":"2022","journal-title":"Eur. J. Hum. Genet."},{"key":"B66","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/j.atherosclerosis.2006.08.039","article-title":"The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population","volume":"193","author":"Hooper","year":"2007","journal-title":"Atherosclerosis"},{"key":"B67","doi-asserted-by":"publisher","first-page":"e208","DOI":"10.1161\/ATVBAHA.120.315708","article-title":"New insight into metformin-induced cholesterol-lowering effect crosstalk between glucose and cholesterol homeostasis via ChREBP (Carbohydrate-Responsive element-binding protein)-mediated PCSK9 (proprotein convertase subtilisin\/kexin type 9) regulation","volume":"41","author":"Hu","year":"2021","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1177\/00220345211015128","article-title":"Pcsk9 knockout aggravated experimental apical periodontitis via LDLR","volume":"101","author":"Huang","year":"2022","journal-title":"J. Dent. Res."},{"key":"B69","doi-asserted-by":"publisher","first-page":"G839","DOI":"10.1152\/ajpgi.00061.2008","article-title":"Development and physiological regulation of intestinal lipid absorption. III. Intestinal transporters and cholesterol absorption","volume":"294","author":"Hui","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"108480","DOI":"10.1016\/j.pharmthera.2023.108480","article-title":"Targeting PCSK9 to tackle cardiovascular disease","volume":"249","author":"Hummelgaard","year":"2023","journal-title":"Pharmacol. Ther."},{"key":"B71","doi-asserted-by":"publisher","first-page":"2153","DOI":"10.1373\/clinchem.2009.129759","article-title":"Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9","volume":"55","author":"Humphries","year":"2009","journal-title":"Clin. Chem."},{"key":"B72","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.arteri.2015.11.001","article-title":"Circulating PCSK9 in patients with type 2 diabetes and related metabolic disorders","volume":"28","author":"Ibarretxe","year":"2016","journal-title":"Clin. Investig. Arterioscler."},{"key":"B73","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/j.cmet.2016.10.001","article-title":"Transintestinal cholesterol transport is active in mice and humans and controls ezetimibe-induced fecal neutral sterol excretion","volume":"24","author":"Jakulj","year":"2016","journal-title":"Cell. Metab."},{"key":"B74","doi-asserted-by":"publisher","first-page":"155527","DOI":"10.1016\/j.metabol.2023.155527","article-title":"TNF\u03b1-induced NLRP3 inflammasome mediates adipocyte dysfunction and activates macrophages through adipocyte-derived lipocalin 2","volume":"142","author":"Javaid","year":"2023","journal-title":"Metabolism"},{"key":"B75","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1007\/s11745-015-4017-9","article-title":"Combined PCSK9 and APOE polymorphisms are genetic risk factors associated with elevated plasma lipid levels in a Thai population","volume":"50","author":"Jeenduang","year":"2015","journal-title":"Lipids"},{"key":"B76","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1194\/jlr.M700443-JLR200","article-title":"Sterol-dependent regulation of proprotein convertase subtilisin\/kexin type 9 expression by sterol-regulatory element binding protein-2","volume":"49","author":"Jeong","year":"2008","journal-title":"J. Lipid Res."},{"key":"B77","doi-asserted-by":"publisher","first-page":"e001632","DOI":"10.1161\/CIRCGENETICS.116.001632","article-title":"PCSK9 loss-of-function variants, low-density lipoprotein cholesterol, and risk of coronary heart disease and stroke: data from 9 studies of blacks and whites","volume":"10","author":"Kent","year":"2017","journal-title":"Circ. Cardiovasc Genet."},{"key":"B78","doi-asserted-by":"publisher","first-page":"e41","DOI":"10.4110\/in.2019.19.e41","article-title":"A critical role of PCSK9 in mediating IL-17-producing T cell responses in hyperlipidemia","volume":"19","author":"Kim","year":"2019","journal-title":"Immune Netw."},{"key":"B79","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.smim.2013.10.009","article-title":"The plasticity of human Treg and Th17 cells and its role in autoimmunity","volume":"25","author":"Kleinewietfeld","year":"2013","journal-title":"Semin. Immunol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1007\/s00125-010-1691-2","article-title":"Cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice","volume":"53","author":"Kruit","year":"2010","journal-title":"Diabetologia"},{"key":"B81","doi-asserted-by":"publisher","first-page":"659","DOI":"10.2337\/db11-1341","article-title":"Loss of both ABCA1 and ABCG1 results in increased disturbances in islet sterol homeostasis, inflammation, and impaired \u03b2-cell function","volume":"61","author":"Kruit","year":"2012","journal-title":"Diabetes"},{"key":"B82","doi-asserted-by":"publisher","first-page":"2995","DOI":"10.1172\/JCI29383","article-title":"Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice","volume":"116","author":"Lagace","year":"2006","journal-title":"J. Clin. Investig."},{"key":"B83","doi-asserted-by":"publisher","first-page":"e89729","DOI":"10.1172\/jci.insight.89729","article-title":"E2F1 inhibits circulating cholesterol clearance by regulating Pcsk9 expression in the liver","volume":"2","author":"Lai","year":"2017","journal-title":"JCI Insight"},{"key":"B84","doi-asserted-by":"publisher","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":"B85","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1016\/j.bbrc.2009.10.138","article-title":"PCSK9 is expressed in pancreatic delta-cells and does not alter insulin secretion","volume":"390","author":"Langhi","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B86","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.atherosclerosis.2020.05.013","article-title":"Molecular mechanism linking a novel PCSK9 copy number variant to severe hypercholesterolemia","volume":"304","author":"Lau","year":"2020","journal-title":"Atherosclerosis"},{"key":"B87","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.1093\/cvr\/cvad041","article-title":"Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function","volume":"119","author":"Laudette","year":"2023","journal-title":"Cardiovasc Res."},{"key":"B88","doi-asserted-by":"publisher","first-page":"23385","DOI":"10.1074\/jbc.M115.642991","article-title":"Plasma membrane tetraspanin CD81 complexes with proprotein convertase subtilisin\/kexin type 9 (PCSK9) and low density lipoprotein receptor (LDLR), and its levels are reduced by PCSK9","volume":"290","author":"Le","year":"2015","journal-title":"J. Biol. Chem."},{"key":"B89","doi-asserted-by":"publisher","first-page":"2265","DOI":"10.1042\/CS20210127","article-title":"Lipotoxicity: a driver of heart failure with preserved ejection fraction?","volume":"135","author":"Leggat","year":"2021","journal-title":"Clin. Sci. (Lond)"},{"key":"B90","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1161\/ATVBAHA.112.300263","article-title":"Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1","volume":"33","author":"Le May","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1161\/ATVBAHA.108.181586","article-title":"Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia","volume":"29","author":"Le May","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B92","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.numecd.2016.12.010","article-title":"Calorically restricted diets decrease PCSK9 in overweight adolescents","volume":"27","author":"Levenson","year":"2017","journal-title":"Nutr. Metab. Cardiovasc Dis."},{"key":"B93","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.atherosclerosis.2013.01.023","article-title":"PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells","volume":"227","author":"Levy","year":"2013","journal-title":"Atherosclerosis"},{"key":"B94","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1161\/01.RES.0000170946.56981.5c","article-title":"New insights into the regulation of HDL metabolism and reverse cholesterol transport","volume":"96","author":"Lewis","year":"2005","journal-title":"Circ. Res."},{"key":"B95","doi-asserted-by":"publisher","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":"B96","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1042\/BJ20111645","article-title":"The novel function of HINFP as a co-activator in sterol-regulated transcription of PCSK9 in HepG2 cells","volume":"443","author":"Li","year":"2012","journal-title":"Biochem. J."},{"key":"B97","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.3390\/antiox10081280","article-title":"Pterostilbene increases LDL metabolism in HL-1 cardiomyocytes by modulating the PCSK9\/HNF1\u03b1\/SREBP2\/LDLR signaling cascade, upregulating epigenetic hsa-miR-335 and hsa-miR-6825, and LDL receptor expression","volume":"10","author":"Lin","year":"2021","journal-title":"Antioxidants (Basel)"},{"key":"B98","doi-asserted-by":"publisher","first-page":"145","DOI":"10.2147\/CPAA.S208033","article-title":"A phase 1, randomized, double-blind, single-dose, placebo-controlled safety, tolerability, and pharmacokinetic\/pharmacodynamic study of evolocumab in healthy Chinese subjects","volume":"11","author":"Liu","year":"2019","journal-title":"Clin. Pharmacol."},{"key":"B99","doi-asserted-by":"publisher","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. Transpl."},{"key":"B100","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1002\/cbin.12018","article-title":"PCSK9 inhibitor attenuates atherosclerosis by regulating SNHG16\/EZH2\/TRAF5-mediated VSMC proliferation, migration, and foam cell formation","volume":"47","author":"Liu","year":"2023","journal-title":"Cell. Biol. Int."},{"key":"B101","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1161\/CIRCRESAHA.121.318241","article-title":"Cardiac energy metabolism in heart failure","volume":"128","author":"Lopaschuk","year":"2021","journal-title":"Circ. Res."},{"key":"B102","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1001\/jama.2016.14568","article-title":"Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis","volume":"316","author":"Lotta","year":"2016","journal-title":"JAMA"},{"key":"B103","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1007\/s12192-011-0265-7","article-title":"Cholesterol induces pancreatic \u03b2 cell apoptosis through oxidative stress pathway","volume":"16","author":"Lu","year":"2011","journal-title":"Cell. Stress Chaperones"},{"key":"B104","doi-asserted-by":"publisher","first-page":"1514","DOI":"10.1016\/j.jmb.2019.09.016","article-title":"Recent insights into mechanisms of \u03b2-cell lipo- and glucolipotoxicity in type 2 diabetes","volume":"432","author":"Lytrivi","year":"2020","journal-title":"J. Mol. Biol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"155291","DOI":"10.1016\/j.metabol.2022.155291","article-title":"Pancreatic PCSK9 controls the organization of the \u03b2-cell secretory pathway via LDLR-cholesterol axis","volume":"136","author":"Marku","year":"2022","journal-title":"Metabolism"},{"key":"B106","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1007\/s00018-022-04237-x","article-title":"PCSK9 acts as a key regulator of A\u03b2 clearance across the blood-brain barrier","volume":"79","author":"Mazura","year":"2022","journal-title":"Cell. Mol. Life Sci."},{"key":"B107","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1111\/1753-0407.12139","article-title":"Variable effects of gender and Western diet on lipid and glucose homeostasis in aged PCSK9-deficient C57BL\/6 mice CSK9PC57BL\/6","volume":"7","author":"Mbikay","year":"2015","journal-title":"J. Diabetes"},{"key":"B108","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/j.febslet.2009.12.018","article-title":"PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities","volume":"584","author":"Mbikay","year":"2010","journal-title":"FEBS Lett."},{"key":"B109","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1139\/Y08-098","article-title":"Animal models of catheter-induced intimal hyperplasia in type 1 and type 2 diabetes and the effects of pharmacologic intervention","volume":"87","author":"McNamara","year":"2009","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"B110","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1161\/CIRCULATIONAHA.117.029785","article-title":"PCSK9 variants, low-density lipoprotein cholesterol, and neurocognitive impairment: reasons for geographic and racial differences in stroke study (REGARDS)","volume":"137","author":"Mefford","year":"2018","journal-title":"Circulation"},{"key":"B111","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1080\/17512433.2022.2132229","article-title":"The role of PCSK9 in NAFLD\/NASH and therapeutic implications of PCSK9 inhibition","volume":"15","author":"Momtazi-Borojeni","year":"2022","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"B112","doi-asserted-by":"publisher","first-page":"100096","DOI":"10.1016\/j.jlr.2021.100096","article-title":"PCSK9 is not secreted from mature differentiated intestinal cells","volume":"62","author":"Moreau","year":"2021","journal-title":"J. Lipid Res."},{"key":"B113","doi-asserted-by":"publisher","first-page":"210","DOI":"10.3390\/metabo12030210","article-title":"Qualitative and quantitative effects of fatty acids involved in heart diseases","volume":"12","author":"Moriyama","year":"2022","journal-title":"Metabolites"},{"key":"B114","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/s41586-021-03534-y","article-title":"In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates","volume":"593","author":"Musunuru","year":"2021","journal-title":"Nature"},{"key":"B115","doi-asserted-by":"publisher","first-page":"2373","DOI":"10.1001\/jama.2016.16951","article-title":"Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial","volume":"316","author":"Nicholls","year":"2016","journal-title":"Jama"},{"key":"B116","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1161\/CIRCULATIONAHA.122.061620","article-title":"Long-term evolocumab in patients with established atherosclerotic cardiovascular disease","volume":"146","author":"ODonoghue","year":"2022","journal-title":"Circulation"},{"key":"B117","doi-asserted-by":"publisher","first-page":"3452","DOI":"10.1210\/jc.2017-00684","article-title":"The effect of PCSK9 loss-of-function variants on the postprandial lipid and ApoB-lipoprotein response","volume":"102","author":"Ooi","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B118","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.cca.2015.03.036","article-title":"Relationship between testosterone, estradiol and circulating PCSK9: cross-sectional and interventional studies in humans","volume":"446","author":"Ooi","year":"2015","journal-title":"Clin. Chim. Acta"},{"key":"B119","doi-asserted-by":"publisher","first-page":"292598","DOI":"10.1155\/2012\/292598","article-title":"Cholesterol: its regulation and role in central nervous system disorders","volume":"2012","author":"Orth","year":"2012","journal-title":"Cholesterol"},{"key":"B120","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1038\/ni1261","article-title":"A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17","volume":"6","author":"Park","year":"2005","journal-title":"Nat. Immunol."},{"key":"B121","doi-asserted-by":"publisher","first-page":"610282","DOI":"10.3389\/fcvm.2020.610282","article-title":"Osteopontin and LDLR are upregulated in hearts of sudden cardiac death victims with heart failure with preserved ejection fraction and diabetes mellitus","volume":"7","author":"Patel","year":"2020","journal-title":"Front. Cardiovasc Med."},{"key":"B122","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1097\/MPA.0000000000000486","article-title":"Cholesterol in pancreatic \u03b2-cell death and dysfunction: underlying mechanisms and pathological implications","volume":"45","author":"Paul","year":"2016","journal-title":"Pancreas"},{"key":"B123","doi-asserted-by":"publisher","first-page":"889972","DOI":"10.3389\/fcell.2022.889972","article-title":"PCSK9 contributes to the cholesterol, glucose, and Insulin2 homeostasis in seminiferous tubules and maintenance of immunotolerance in testis","volume":"10","author":"Pelletier","year":"2022","journal-title":"Front. Cell. Dev. Biol."},{"key":"B124","doi-asserted-by":"publisher","first-page":"2149","DOI":"10.1016\/j.bbadis.2019.04.012","article-title":"Norata GD: cholesterol metabolism, pancreatic \u03b2-cell function and diabetes","volume":"1865","author":"Perego","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B125","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1161\/CIRCULATIONAHA.122.062557","article-title":"Alirocumab and coronary atherosclerosis in asymptomatic patients with familial hypercholesterolemia: the ARCHITECT study","volume":"147","author":"P\u00e9rez de Isla","year":"2023","journal-title":"Circulation"},{"key":"B126","doi-asserted-by":"publisher","first-page":"2625","DOI":"10.1172\/JCI43068","article-title":"The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction","volume":"121","author":"Perman","year":"2011","journal-title":"J. Clin. Investig."},{"key":"B127","doi-asserted-by":"publisher","first-page":"11179","DOI":"10.3390\/ijms222011179","article-title":"Platelet-derived PCSK9 is associated with LDL metabolism and modulates atherothrombotic mechanisms in coronary artery disease","volume":"22","author":"Petersen-Uribe","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B128","doi-asserted-by":"publisher","first-page":"158968","DOI":"10.1016\/j.bbalip.2021.158968","article-title":"Substantial PCSK9 inactivation in \u03b2-cells does not modify glucose homeostasis or insulin secretion in mice","volume":"1866","author":"Peyot","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Cell. Biol. Lipids"},{"key":"B129","doi-asserted-by":"publisher","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":"B130","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1111\/j.1471-4159.2006.03928.x","article-title":"Implication of the proprotein convertase NARC-1\/PCSK9 in the development of the nervous system","volume":"98","author":"Poirier","year":"2006","journal-title":"J. Neurochem."},{"key":"B131","doi-asserted-by":"publisher","first-page":"e023328","DOI":"10.1161\/JAHA.121.023328","article-title":"Effects of PCSK9 targeting: alleviating oxidation, inflammation, and atherosclerosis","volume":"11","author":"Punch","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"B132","doi-asserted-by":"publisher","first-page":"2234","DOI":"10.1016\/j.numecd.2021.03.026","article-title":"The effect of PCSK9 inhibitors on brain stroke prevention: a systematic review and meta-analysis","volume":"31","author":"Qin","year":"2021","journal-title":"Nutr. Metab. Cardiovasc Dis."},{"key":"B133","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1001\/jama.2022.5218","article-title":"Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial","volume":"327","author":"R\u00e4ber","year":"2022","journal-title":"Jama"},{"key":"B134","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.atherosclerosis.2021.03.044","article-title":"Effects of proprotein convertase subtilisin kexin type 9 modulation in human pancreatic beta cells function","volume":"326","author":"Ramin-Mangata","year":"2021","journal-title":"Atherosclerosis"},{"key":"B135","doi-asserted-by":"publisher","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. U. S. A."},{"key":"B136","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1056\/NEJMoa1615758","article-title":"Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol","volume":"376","author":"Ray","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B137","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1093\/eurheartj\/ehac594","article-title":"Inclisiran and cardiovascular events: a patient-level analysis of phase III trials","volume":"44","author":"Ray","year":"","journal-title":"Eur. Heart J."},{"key":"B138","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1001\/jamacardio.2019.3502","article-title":"Effect of 1 or 2 doses of inclisiran on low-density lipoprotein cholesterol levels: one-year follow-up of the ORION-1 randomized clinical trial","volume":"4","author":"Ray","year":"2019","journal-title":"JAMA Cardiol."},{"key":"B139","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/S2213-8587(22)00353-9","article-title":"Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial","volume":"11","author":"Ray","year":"","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B140","doi-asserted-by":"publisher","first-page":"30949","DOI":"10.1074\/jbc.M111.230508","article-title":"Fatty acid synthase modulates homeostatic responses to myocardial stress","volume":"286","author":"Razani","year":"2011","journal-title":"J. Biol. Chem."},{"key":"B141","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.jacc.2016.11.037","article-title":"Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials","volume":"69","author":"Robinson","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"B142","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1194\/jlr.M061952","article-title":"PCSK9 deficiency unmasks a sex- and tissue-specific subcellular distribution of the LDL and VLDL receptors in mice","volume":"56","author":"Roubtsova","year":"2015","journal-title":"J. Lipid Res."},{"key":"B143","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1161\/ATVBAHA.110.220988","article-title":"Circulating proprotein convertase subtilisin\/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue","volume":"31","author":"Roubtsova","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B144","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1194\/jlr.M014118","article-title":"PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke","volume":"52","author":"Rousselet","year":"2011","journal-title":"J. Lipid Res."},{"key":"B145","doi-asserted-by":"publisher","first-page":"2353","DOI":"10.1126\/science.1078124","article-title":"Structure of the LDL receptor extracellular domain at endosomal pH","volume":"298","author":"Rudenko","year":"2002","journal-title":"Science"},{"key":"B146","doi-asserted-by":"publisher","first-page":"4521","DOI":"10.1210\/en.2009-0252","article-title":"Low- and high-density lipoproteins modulate function, apoptosis, and proliferation of primary human and murine pancreatic beta-cells","volume":"150","author":"R\u00fctti","year":"2009","journal-title":"Endocrinology"},{"key":"B147","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1056\/NEJMoa1615664","article-title":"Evolocumab and clinical outcomes in patients with cardiovascular disease","volume":"376","author":"Sabatine","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B148","doi-asserted-by":"publisher","first-page":"11795514221093317","DOI":"10.1177\/11795514221093317","article-title":"The relationship of circulating proprotein convertase subtilisin\/kexin type 9 with TSH and lipid profile in newly diagnosed patients with subclinical and overt hypothyroidism","volume":"15","author":"Sadik","year":"2022","journal-title":"Clin. Med. Insights Endocrinol. Diabetes"},{"key":"B149","doi-asserted-by":"publisher","first-page":"695792","DOI":"10.3389\/fmed.2021.695792","article-title":"The diabetic cardiomyopathy: the contributing pathophysiological mechanisms","volume":"8","author":"Salvatore","year":"2021","journal-title":"Front. Med. (Lausanne)"},{"key":"B150","doi-asserted-by":"publisher","first-page":"915","DOI":"10.3390\/biom12070915","article-title":"Expression of a PCSK9 gain-of-function mutation in C57bl\/6J mice to facilitate angiotensin II-induced AAAs","volume":"12","author":"Sawada","year":"2022","journal-title":"Biomolecules"},{"key":"B151","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1002\/mrd.21208","article-title":"Lipid accumulation and metabolism in polychaete spermatogenesis: role of the large discoidal lipoprotein","volume":"77","author":"Schenk","year":"2010","journal-title":"Mol. Reprod. Dev."},{"key":"B152","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/s41586-019-1100-z","article-title":"Nitrosative stress drives heart failure with preserved ejection fraction","volume":"568","author":"Schiattarella","year":"2019","journal-title":"Nature"},{"key":"B153","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/S2213-8587(16)30396-5","article-title":"PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study","volume":"5","author":"Schmidt","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B154","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/j.bbrc.2008.04.004","article-title":"Secreted proprotein convertase subtilisin\/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo","volume":"370","author":"Schmidt","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B155","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1073\/pnas.0335507100","article-title":"The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation","volume":"100","author":"Seidah","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B156","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1007\/s11886-023-01918-2","article-title":"Pleiotropy of PCSK9: functions in extrahepatic tissues","volume":"25","author":"\u015eener","year":"2023","journal-title":"Curr. Cardiol. Rep."},{"key":"B157","doi-asserted-by":"publisher","first-page":"e30942","DOI":"10.7759\/cureus.30942","article-title":"Neurocognitive impairment in cardiovascular disease patients taking statins versus proprotein convertase subtilisin\/kexin type 9 (PCSK9) inhibitors: a systematic review","volume":"14","author":"Shahid","year":"2022","journal-title":"Cureus"},{"key":"B158","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1007\/978-1-0716-1920-9_21","article-title":"Assessment of metabolic regulation by estrogen receptors","volume":"2418","author":"Sharma","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"B159","doi-asserted-by":"publisher","first-page":"19266","DOI":"10.1074\/jbc.M112.363382","article-title":"Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin\/kexin type 9 (PCSK9)","volume":"287","author":"Sharotri","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B160","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1016\/j.kint.2023.06.024","article-title":"Proprotein convertase subtilisin\/kexin type 9 targets megalin in the kidney proximal tubule and aggravates proteinuria in nephrotic syndrome","volume":"104","author":"Skeby","year":"2023","journal-title":"Kidney Int."},{"key":"B161","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1161\/CIRCRESAHA.118.313648","article-title":"Hepatic glucagon signaling regulates PCSK9 and low-density lipoprotein cholesterol","volume":"124","author":"Spolitu","year":"2019","journal-title":"Circ. Res."},{"key":"B162","doi-asserted-by":"publisher","first-page":"506","DOI":"10.20452\/pamw.4044","article-title":"Effect of long-term physical activity on PCSK9, high- and low-density lipoprotein cholesterol, and lipoprotein(a) levels: a prospective observational trial","volume":"127","author":"Sponder","year":"2017","journal-title":"Pol. Arch. Intern Med."},{"key":"B163","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1016\/S0140-6736(05)61032-X","article-title":"Type 2 diabetes: principles of pathogenesis and therapy","volume":"365","author":"Stumvoll","year":"2005","journal-title":"Lancet"},{"key":"B164","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1093\/infdis\/jix574","article-title":"Role of PCSK9 in the development of mouse periodontitis before and after treatment: a double-edged sword","volume":"217","author":"Sun","year":"2018","journal-title":"J. Infect. Dis."},{"key":"B165","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1007\/s00109-010-0720-4","article-title":"Increased CD36 expression in middle-aged mice contributes to obesity-related cardiac hypertrophy in the absence of cardiac dysfunction","volume":"89","author":"Sung","year":"2011","journal-title":"J. Mol. Med. Berl."},{"key":"B166","doi-asserted-by":"publisher","first-page":"166215","DOI":"10.1016\/j.bbadis.2021.166215","article-title":"Regulation of the expression of cholesterol transporters by lipid-lowering drugs ezetimibe and pemafibrate in rat liver and intestine","volume":"1867","author":"Tanaka","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B167","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1080\/1061186X.2022.2092622","article-title":"Molecular and cellular biology of PCSK9: impact on glucose homeostasis","volume":"30","author":"Tch\u00e9oubi","year":"2022","journal-title":"J. Drug Target"},{"key":"B168","doi-asserted-by":"publisher","first-page":"136","DOI":"10.3389\/fgene.2015.00136","article-title":"PCSK9 variation and association with blood pressure in African Americans: preliminary findings from the HyperGEN and REGARDS studies","volume":"6","author":"Tran","year":"2015","journal-title":"Front. Genet."},{"key":"B169","doi-asserted-by":"publisher","first-page":"155247","DOI":"10.1016\/j.metabol.2022.155247","article-title":"Lipid-induced glucose intolerance is driven by impaired glucose kinetics and insulin metabolism in healthy individuals","volume":"134","author":"Tric\u00f2","year":"2022","journal-title":"Metabolism"},{"key":"B170","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1001\/jamacardio.2022.4798","article-title":"Association of PCSK9 loss-of-function variants with risk of heart failure","volume":"8","author":"Truds\u00f8","year":"2023","journal-title":"JAMA Cardiol."},{"key":"B171","doi-asserted-by":"publisher","first-page":"19211","DOI":"10.1074\/jbc.M109.014860","article-title":"Activation of the liver X receptor stimulates trans-intestinal excretion of plasma cholesterol","volume":"284","author":"van der Veen","year":"2009","journal-title":"J. Biol. Chem."},{"key":"B172","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1053\/j.gastro.2007.06.019","article-title":"Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice","volume":"133","author":"van der Velde","year":"2007","journal-title":"Gastroenterology"},{"key":"B173","doi-asserted-by":"publisher","first-page":"19295","DOI":"10.1038\/srep19295","article-title":"Transcriptome profiling unveils the role of cholesterol in IL-17A signaling in psoriasis","volume":"6","author":"Varshney","year":"2016","journal-title":"Sci. Rep."},{"key":"B174","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1016\/j.cell.2015.10.068","article-title":"CD5L\/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity","volume":"163","author":"Wang","year":"2015","journal-title":"Cell."},{"key":"B175","doi-asserted-by":"publisher","first-page":"7685796","DOI":"10.1155\/2022\/7685796","article-title":"PCSK9 modulates macrophage polarization-mediated ventricular remodeling after myocardial infarction","volume":"2022","author":"Wang","year":"2022","journal-title":"J. Immunol. Res."},{"key":"B176","doi-asserted-by":"publisher","first-page":"153688","DOI":"10.1016\/j.phymed.2021.153688","article-title":"Gypenoside LVI improves hepatic LDL uptake by decreasing PCSK9 and upregulating LDLR expression","volume":"91","author":"Wang","year":"2021","journal-title":"Phytomedicine"},{"key":"B177","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1007\/s00395-020-00832-w","article-title":"PCSK9 regulates pyroptosis via mtDNA damage in chronic myocardial ischemia","volume":"115","author":"Wang","year":"2020","journal-title":"Basic Res. Cardiol."},{"key":"B178","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.jacl.2016.09.015","article-title":"Predicting proprotein convertase subtilisin kexin type-9 loss of function mutations using plasma PCSK9 concentration","volume":"11","author":"Wanneh","year":"2017","journal-title":"J. Clin. Lipidol."},{"key":"B179","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1038\/s41385-020-0330-6","article-title":"Microbiota-dependent expansion of testicular IL-17-producing V\u03b36(+) \u03b3\u03b4 T cells upon puberty promotes local tissue immune surveillance","volume":"14","author":"Wilharm","year":"2021","journal-title":"Mucosal Immunol."},{"key":"B180","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1038\/hr.2016.38","article-title":"Plasma PCSK9 level is unrelated to blood pressure and not associated independently with carotid intima-media thickness in hypertensives","volume":"39","author":"Yang","year":"2016","journal-title":"Hypertens. Res."},{"key":"B181","doi-asserted-by":"publisher","first-page":"60","DOI":"10.3892\/ijmm.2023.5263","article-title":"Interaction between apical periodontitis and systemic disease (Review)","volume":"52","author":"Ye","year":"2023","journal-title":"Int. J. Mol. Med."},{"key":"B182","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1002\/hep.22354","article-title":"Proprotein convertase subtilisin\/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration","volume":"48","author":"Zaid","year":"2008","journal-title":"Hepatology"},{"key":"B183","doi-asserted-by":"publisher","first-page":"155165","DOI":"10.1016\/j.metabol.2022.155165","article-title":"Endothelial sodium channel activation mediates DOCA-salt-induced endothelial cell and arterial stiffening","volume":"130","author":"Zhang","year":"2022","journal-title":"Metabolism"},{"key":"B184","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1086\/507488","article-title":"Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote","volume":"79","author":"Zhao","year":"2006","journal-title":"Am. J. Hum. Genet."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1413123\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T04:50:25Z","timestamp":1722315025000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1413123\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,30]]},"references-count":184,"alternative-id":["10.3389\/fphar.2024.1413123"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1413123","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,30]]},"article-number":"1413123"}}