{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:21:11Z","timestamp":1793143271491,"version":"4.5.0"},"reference-count":30,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T00:00:00Z","timestamp":1601251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Since emerging evidence suggests a protective role of proprotein convertase subtilisin\/kexin type 9 (PCSK9) on hepatitis C virus (HCV) infection, the aim of the present study was to evaluate the correlation between PCSK9 and HCV infection in hepatocellular carcinoma (HCC) patients. Methods: In this retrospective study, PCSK9 levels were evaluated by ELISA, in plasma samples from control (n = 24) and 178 patients diagnosed for HCC, cirrhosis, or chronic hepatitis, either positive or negative for HCV. Results: HCV positive patients (HCV+) presented with higher PCSK9 levels compared to HCV negative individuals (HCV-), 325.2 \u00b1 117.7 ng\/mL and 256.7 \u00b1 139.5 ng\/mL, respectively. This difference was maintained in the presence of HCC, although this disease significantly reduced PCSK9 levels. By univariate analysis, a positive correlation between PCSK9 and HCV viral titer was found, being G2 genotype the most-potent inducer of PCSK9 among other genotypes. This induction was not associated with changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). A negative correlation was also found between PCSK9 levels and liver impairment, assessed by Model for End-Stage Liver Disease (MELD). Finally, a multivariate correlation analysis corrected for age, TC, LDL-C, and sex, demonstrated, in the whole cohort, a positive association between PCSK9 and HCV and a negative with HCC. Conclusions: taken together, our study reveals that HCV raised PCSK9 in both the presence and absence of HCC.<\/jats:p>","DOI":"10.3390\/jcm9103134","type":"journal-article","created":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T10:39:58Z","timestamp":1601289598000},"page":"3134","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["PCSK9 Levels Are Raised in Chronic HCV Patients with Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"9","author":[{"given":"Silvano","family":"Fasolato","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Padova, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Pigozzo","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Padova, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Pontisso","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Padova, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Angeli","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Padova, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0195-7061","authenticated-orcid":false,"given":"Massimiliano","family":"Ruscica","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3187-2894","authenticated-orcid":false,"given":"Edoardo","family":"Savarino","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6398-8237","authenticated-orcid":false,"given":"Sara","family":"De Martin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4236-4414","authenticated-orcid":false,"given":"Maria Giovanna","family":"Lupo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8898-7441","authenticated-orcid":false,"given":"Nicola","family":"Ferri","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,28]]},"reference":[{"key":"ref_1","unstructured":"European Association for the Study of the Liver (2018). EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol., 69, 182\u2013236."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1056\/NEJMra1001683","article-title":"Hepatocellular carcinoma","volume":"365","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1002\/cncr.29936","article-title":"Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer","volume":"122","author":"Ryerson","year":"2016","journal-title":"Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1002\/hep.510290604","article-title":"High prevalence of multinodular hepatocellular carcinoma in patients with cirrhosis attributable to multiple risk factors","volume":"29","author":"Fasani","year":"1999","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1159\/000048270","article-title":"Hepatocellular carcinoma associated with hepatitis C virus infection in Japan: Projection to other countries in the foreseeable future","volume":"62","author":"Yoshizawa","year":"2002","journal-title":"Oncology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"892","DOI":"10.3390\/biology3040892","article-title":"Hepatitis C virus life cycle and lipid metabolism","volume":"3","author":"Popescu","year":"2014","journal-title":"Biology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1002\/hep.28123","article-title":"Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009","volume":"62","author":"Younossi","year":"2015","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1073\/pnas.0409736102","article-title":"Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment","volume":"102","author":"Maxwell","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1080\/07853890.2016.1188328","article-title":"Liver fat accumulation is associated with circulating PCSK9","volume":"48","author":"Ruscica","year":"2016","journal-title":"Ann. Med."},{"key":"ref_10","first-page":"19","article-title":"Proprotein convertase subtilisin kexin type 9 and high-density lipoprotein metabolism: Experimental animal models and clinical evidence","volume":"173","author":"Ferri","year":"2016","journal-title":"Transl. Res. J. Lab. Clin. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1007\/s12020-016-0939-0","article-title":"Proprotein convertase subtilisin\/kexin type 9 (PCSK9) and metabolic syndrome: Insights on insulin resistance, inflammation, and atherogenic dyslipidemia","volume":"54","author":"Ferri","year":"2016","journal-title":"Endocrine"},{"key":"ref_12","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":"Labonte","year":"2009","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ramanathan, A., Gusarova, V., Stahl, N., Gurnett-Bander, A., and Kyratsous, C.A. (2016). Alirocumab, a Therapeutic Human Antibody to PCSK9, Does Not Affect CD81 Levels or Hepatitis C Virus Entry and Replication into Hepatocytes. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0154498"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.atherosclerosis.2016.11.019","article-title":"Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages","volume":"256","author":"Adorni","year":"2017","journal-title":"Atherosclerosis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.bbrc.2018.01.176","article-title":"Hepatitis C virus regulates proprotein convertase subtilisin\/kexin type 9 promoter activity","volume":"496","author":"Li","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1099\/jgv.0.000987","article-title":"Proprotein convertase subtilisin\/kexin type 9 inhibits hepatitis C virus replication through interacting with NS5A","volume":"99","author":"Li","year":"2018","journal-title":"J. Gen. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ruscica, M., Ferri, N., Fogacci, F., Rosticci, M., Botta, M., Marchiano, S., Magni, P., D\u2019Addato, S., Giovannini, M., and Borghi, C. (2017). Circulating Levels of Proprotein Convertase Subtilisin\/Kexin Type 9 and Arterial Stiffness in a Large Population Sample: Data From the Brisighella Heart Study. J. Am. Heart Assoc., 6.","DOI":"10.1161\/JAHA.117.005764"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1128\/JVI.02727-13","article-title":"Hepatitis C virus stimulates low-density lipoprotein receptor expression to facilitate viral propagation","volume":"88","author":"Syed","year":"2014","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.jhep.2015.07.006","article-title":"Statin use and the risk of cirrhosis development in patients with hepatitis C virus infection","volume":"63","author":"Yang","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1200\/JCO.2012.44.6831","article-title":"Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection","volume":"31","author":"Tsan","year":"2013","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15865","DOI":"10.1073\/pnas.2237238100","article-title":"Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation","volume":"100","author":"Ye","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.antiviral.2016.02.006","article-title":"Statins can exert dual, concentration dependent effects on HCV entry in vitro","volume":"128","author":"Blanchet","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1194\/jlr.M700437-JLR200","article-title":"Atorvastatin increases human serum levels of proprotein convertase subtilisin\/kexin type 9","volume":"49","author":"Careskey","year":"2008","journal-title":"J Lipid Res"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.phrs.2017.05.021","article-title":"Geranylgeraniol prevents the simvastatin-induced PCSK9 expression: Role of the small G protein Rac1","volume":"122","author":"Ferri","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bhat, M., Skill, N., Marcus, V., Deschenes, M., Tan, X., Bouteaud, J., Negi, S., Awan, Z., Aikin, R., and Kwan, J. (2015). Decreased PCSK9 expression in human hepatocellular carcinoma. BMC Gastroenterol., 15.","DOI":"10.1186\/s12876-015-0371-6"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ebiom.2017.08.020","article-title":"Treatment-Induced Viral Cure of Hepatitis C Virus-Infected Patients Involves a Dynamic Interplay among three Important Molecular Players in Lipid Homeostasis: Circulating microRNA (miR)-24, miR-223, and Proprotein Convertase Subtilisin\/Kexin Type 9","volume":"23","author":"Hyrina","year":"2017","journal-title":"EBioMedicine"},{"key":"ref_27","doi-asserted-by":"crossref","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":"ref_28","doi-asserted-by":"crossref","first-page":"3508","DOI":"10.1074\/jbc.M115.664706","article-title":"Suppressor of Cytokine Signaling-3 (SOCS-3) Induces Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Expression in Hepatic HepG2 Cell Line","volume":"291","author":"Ruscica","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1194\/jlr.M052969","article-title":"Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1alpha in normolipidemic mice","volume":"56","author":"Shende","year":"2015","journal-title":"J. Lipid. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jhep.2015.08.027","article-title":"Dysregulation of distal cholesterol biosynthesis in association with relapse and advanced disease in CHC genotype 2 and 3 treated with sofosbuvir and ribavirin","volume":"64","author":"Younossi","year":"2016","journal-title":"J. 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