{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:11:19Z","timestamp":1790730679341,"version":"4.1.0"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T00:00:00Z","timestamp":1644537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011725","name":"Servier","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background and aims<\/jats:title><jats:p>Nonalcoholic Steatohepatitis (NASH) is a major cause of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma resulting ultimately in increased liver-related mortality. Fibrosis is the main driver of mortality in NASH. Procollagen C-Proteinase Enhancer-1 (PCPE-1) plays a key role in procollagen maturation and collagen fibril formation. To assess its role in liver fibrosis and NASH progression, knock-out mice were evaluated in a dietary NASH model.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>Global constitutive<jats:italic>Pcolce<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup>and WT male mice were fed with a Choline Deficient Amino acid defined High Fat Diet (CDA HFD) for 8 weeks. Liver triglycerides, steatosis, inflammation and fibrosis were assessed at histological, biochemical and gene expression levels. In addition, human liver samples from control and NASH patients were used to evaluate the expression of PCPE-1 at both mRNA and protein levels.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p><jats:italic>Pcolce<\/jats:italic>gene deficiency prevented diet-induced liver enlargement but not liver dysfunction. Furthermore, liver triglycerides, steatosis and inflammation were not modified in<jats:italic>Pcolce<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup>male mice compared to WT under CDA HFD. However, a significant decrease in liver fibrosis was observed in<jats:italic>Pcolce<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup>mice compared to WT under NASH diet, associated with a decrease in total and insoluble collagen content without any significant modifications in the expression of genes involved in fibrosis and extracellular matrix remodeling. Finally, PCPE-1 protein expression was increased in cirrhotic liver samples from both NASH and Hepatitis C patients.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>Pcolce<\/jats:italic>deficiency limits fibrosis but not NASH progression in CDA HFD fed mice.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0263828","type":"journal-article","created":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T18:31:22Z","timestamp":1644604282000},"page":"e0263828","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Procollagen C-Proteinase Enhancer-1 (PCPE-1) deficiency in mice reduces liver fibrosis but not NASH progression"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3685-4473","authenticated-orcid":true,"given":"Patricia","family":"Sansilvestri Morel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Duvivier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Bertin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Provost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6928-7431","authenticated-orcid":true,"given":"Adel","family":"Hammoutene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwige-Ludiwyne","family":"Hubert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arantxa","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Tupinon-Mathieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Paradis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Delerive","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,2,11]]},"reference":[{"key":"pone.0263828.ref001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nrdp.2015.80","article-title":"Nonalcoholic fatty liver disease","volume":"1","author":"EM Brunt","year":"2015","journal-title":"Nat Rev Dis Primers"},{"key":"pone.0263828.ref002","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1056\/NEJMra1503519","article-title":"Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis","volume":"377","author":"AM Diehl","year":"2017","journal-title":"N Engl J Med"},{"key":"pone.0263828.ref003","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1053\/j.gastro.2015.04.043","article-title":"Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease","volume":"149","author":"P Angulo","year":"2015","journal-title":"Gastroenterology"},{"key":"pone.0263828.ref004","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1016\/j.jhep.2017.07.027","article-title":"Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD","volume":"67","author":"H Hagstr\u00f6m","year":"2017","journal-title":"J Hepatol"},{"key":"pone.0263828.ref005","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41575-018-0009-6","article-title":"Triggering and resolution of inflammation in NASH","volume":"15","author":"S Schuster","year":"2018","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"pone.0263828.ref006","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1053\/j.gastro.2019.11.311","article-title":"Mechanisms of fibrosis development in nonalcoholic steatohepatitis","volume":"158","author":"RF Schwabe","year":"2020","journal-title":"Gastroenterology"},{"key":"pone.0263828.ref007","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1002\/hep.28918","article-title":"The hepatic \u201cmatrisome\u201d responds dynamically to injury: characterization of transitional changes to the extracellular matrix in mice","volume":"65","author":"VL Massey","year":"2017","journal-title":"Hepatology"},{"key":"pone.0263828.ref008","doi-asserted-by":"crossref","first-page":"98","DOI":"10.18632\/aging.101124","article-title":"Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling","volume":"9","author":"B Delire","year":"2016","journal-title":"Aging"},{"key":"pone.0263828.ref009","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/j.1432-1033.1989.tb15184.x","article-title":"Type I procollagen C-proteinase from mouse fibroblasts. Purification and demonstration of a 55-kDa enhancer glycoprotein","volume":"186","author":"E Kessler","year":"1989","journal-title":"Eur J Biochem"},{"key":"pone.0263828.ref010","first-page":"149","volume-title":"Collagen. Topics in Current Chemistry","author":"DS Greenspan","year":"2005"},{"key":"pone.0263828.ref011","doi-asserted-by":"crossref","first-page":"24188","DOI":"10.1074\/jbc.M501486200","article-title":"Substrate-specific modulation of a multisubstrate proteinase","volume":"280","author":"C Moali","year":"2005","journal-title":"J Biol Chem"},{"key":"pone.0263828.ref012","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1016\/j.str.2018.06.011","article-title":"Structural basis for the acceleration of procollagen processing by Procollagen C-Proteinase Enhancer-1","volume":"26","author":"D Pulido","year":"2018","journal-title":"Structure"},{"key":"pone.0263828.ref013","doi-asserted-by":"crossref","first-page":"49820","DOI":"10.1074\/jbc.M209891200","article-title":"PCOLCE2 encodes a functional procollagen C-proteinase enhancer (PCPE2) that is a collagen-binding protein differing in distribution of expression and post-translational modification from the previously described PCPE-1","volume":"277","author":"BM Steiglitz","year":"2002","journal-title":"J Biol Chem"},{"key":"pone.0263828.ref014","doi-asserted-by":"crossref","first-page":"15496","DOI":"10.1074\/jbc.M115.646240","article-title":"Procollagen C-endopeptidase enhancer protein 2 (PCPE2) reduces atherosclerosis in mice by enhancing scavenger receptor class B1 (SR-BI)-mediated high-density lipoprotein (HDL)-cholesteryl ester uptake","volume":"290","author":"RD Pollard","year":"2015","journal-title":"J Biol Chem"},{"key":"pone.0263828.ref015","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.biocel.2005.10.007","article-title":"Expression of Procollagen C-Proteinase enhancer-1 in the remodeling heart is stimulated by aldoscterone","volume":"38","author":"G. Kessler-Icekson","year":"2006","journal-title":"Int J Biochem Cell Biol"},{"key":"pone.0263828.ref016","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1111\/nep.13521","article-title":"Elevated serum levels of Procollagen C-Proteinase Enhancer-1 in patients with chronic kidney disease is associated with a declining glomerular filtration rate","volume":"24","author":"G Ozkan","year":"2019","journal-title":"Nephrology"},{"key":"pone.0263828.ref017","doi-asserted-by":"crossref","first-page":"819","DOI":"10.15252\/msb.20156123","article-title":"Time- and compartment- resolved proteome profiling of the extracellular niche in lung injury and repair","volume":"11","author":"HB Schiller","year":"2015","journal-title":"Mol Syst Biol"},{"key":"pone.0263828.ref018","doi-asserted-by":"crossref","first-page":"6712","DOI":"10.1167\/iovs.13-13800","article-title":"Upregulation of Bone Morphogenetic Protein-1\/ mammalian tolloid and Procollagen C-Proteinase Enhancer-1 in corneal scarring","volume":"55","author":"F Malecaze","year":"2014","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0263828.ref019","doi-asserted-by":"crossref","first-page":"100062","DOI":"10.1016\/j.mbplus.2021.100062","article-title":"Procollagen C-Proteinase Enhancer-1, a potential biomarker and therapeutic target for fibrosis","volume":"11","author":"P Lagoutte","year":"2021","journal-title":"Matrix Biol Plus"},{"key":"pone.0263828.ref020","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1002\/hep.510260312","article-title":"Up-regulation of type I procollagen C-proteinase enhancer protein messenger RNA in rats with CCl4-induced liver fibrosis","volume":"26","author":"I Ogata","year":"1997","journal-title":"Hepatology"},{"key":"pone.0263828.ref021","first-page":"1","article-title":"Procollagen C-proteinase enhancer 1 (PCPE-1) as a plasma marker of muscle and liver fibrosis in mice","volume":"11","author":"E Hassoun","year":"2016","journal-title":"PLOS One"},{"key":"pone.0263828.ref022","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/toxsci\/kfv214","article-title":"Gene expression patterns associated with histopathology in toxic liver fibrosis","volume":"149","author":"DL Ippolito","year":"2016","journal-title":"Toxicol Sci"},{"key":"pone.0263828.ref023","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.dib.2017.08.047","article-title":"Data comparing the plasma levels of procollagen C-proteinase enhancer 1 (PCPE-1) in healthy individuals and liver fibrosis patients","volume":"14","author":"E Hassoun","year":"2017","journal-title":"Data in brief"},{"key":"pone.0263828.ref024","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1097\/MEG.0000000000001123","article-title":"Evaluation of serum procollagen C-proteinase enhancer 1 level as a fibrosis marker in patients with chronic hepatitis B","volume":"30","author":"O Gokce","year":"2018","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"pone.0263828.ref025","doi-asserted-by":"crossref","first-page":"e703","DOI":"10.1097\/FJC.0000000000001122","article-title":"Deficiency of procollagen C-proteinase enhancer 1 (PCPE-1) in mouse has no impact on cardiac collagen and function under basal conditions","volume":"78","author":"P Sansilvestri-Morel","year":"2021","journal-title":"J Cardiovasc Pharmacol"},{"key":"pone.0263828.ref026","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s00795-013-0016-1","article-title":"A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma","volume":"46","author":"M Fujii","year":"2013","journal-title":"Med Mol Morphol"},{"key":"pone.0263828.ref027","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s12876-020-01356-2","article-title":"Human translatability of the GAN diet-induced obese mouse model of nonalcoholic steatohepatitis","volume":"20","author":"HH Hansen","year":"2020","journal-title":"BMC Gastroenterol"},{"key":"pone.0263828.ref028","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/iep.12008","article-title":"An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis","volume":"94","author":"M Matsumoto","year":"2013","journal-title":"Int J Exp Path"},{"key":"pone.0263828.ref029","doi-asserted-by":"crossref","first-page":"770","DOI":"10.3389\/fphys.2019.00770","article-title":"The influence of different fat sources on steatohepatitis and fibrosis development in the western diet mouse model of non-alcoholic steatohepatitis (NASH)","volume":"10","author":"HK Drescher","year":"2019","journal-title":"Front Physiol"},{"issue":"6","key":"pone.0263828.ref030","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"DE Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"pone.0263828.ref031","doi-asserted-by":"crossref","first-page":"H234","DOI":"10.1152\/ajpheart.00227.2012","article-title":"Effect of the absence of procollagen C-endopeptidase enhancer-2 on myocardial collagen accumulation in chronic pressure overload","volume":"303","author":"CF Baicu","year":"2012","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"pone.0263828.ref032","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0021-9258(18)56248-7","article-title":"The determination of collagen and elastin in tissues","volume":"186","author":"RE Neuman","year":"1950","journal-title":"J Biol Chem"},{"key":"pone.0263828.ref033","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.jhep.2017.10.031","article-title":"Preclinical models of nonalcoholic fatty liver disease","volume":"68","author":"PK Santhekadur","year":"2018","journal-title":"J Hepatol"},{"key":"pone.0263828.ref034","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1128\/MCB.26.1.238-249.2006","article-title":"Procollagen C proteinase enhancer 1 genes are important determinants of the mechanical properties and geometry of bone and the ultrastructure of connective tissues","volume":"26","author":"BM Steiglitz","year":"2006","journal-title":"Mol Cell Biol"},{"key":"pone.0263828.ref035","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.molcel.2019.07.028","article-title":"Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis","volume":"75","author":"X Xiong","year":"2019","journal-title":"Mol Cell"},{"key":"pone.0263828.ref036","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s00441-017-2689-6","article-title":"Procollagen C-Proteinase Enhancer 1 (PCPE-1) functions as an anti-angiogenic factor and enhances epithelial recovery in injured cornea","volume":"370","author":"D Massoudi","year":"2017","journal-title":"Cell Tissue Res"},{"key":"pone.0263828.ref037","first-page":"1","article-title":"Longitudinal characterization of diet-induced genetic murine models of non-alcoholic steatohepatitis with metabolic, histological, and transcriptomic hallmarks of human diets","volume":"8","author":"N Abe","year":"2019","journal-title":"Biol Open"},{"key":"pone.0263828.ref038","doi-asserted-by":"crossref","first-page":"8525","DOI":"10.3748\/wjg.v20.i26.8525","article-title":"High fat diet feeding result in gender specific steatohepatitis and inflammasome activation","volume":"20","author":"M Ganz","year":"2014","journal-title":"World J Gastroenterol"},{"key":"pone.0263828.ref039","doi-asserted-by":"crossref","first-page":"e0229896","DOI":"10.1371\/journal.pone.0229896","article-title":"Gender differences in diet-induced steatotic disease in Cyp2b-null mice","volume":"15","author":"MM Heintz","year":"2020","journal-title":"PLOS One"},{"key":"pone.0263828.ref040","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1194\/jlr.M016527","article-title":"Disruption of the murine procollagen C-proteinase enhancer 2 gene causes accumulation of pro-apoA-I and increased HDL levels","volume":"52","author":"OL Francone","year":"2011","journal-title":"J Lipid Res"},{"key":"pone.0263828.ref041","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.jhep.2013.04.027","article-title":"A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver","volume":"59","author":"R Pais","year":"2013","journal-title":"J Hepatol"},{"key":"pone.0263828.ref042","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jhep.2015.08.014","article-title":"Collagen and tissue turnover as a function of age: implications for fibrosis","volume":"64","author":"MA Karsdal","year":"2016","journal-title":"J Hepatol"},{"key":"pone.0263828.ref043","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1055\/s-0035-1550065","article-title":"Fibrosis in nonalcoholic fatty liver disease; mechanisms and clinical implications","volume":"35","author":"P Angulo","year":"2015","journal-title":"Semin Liver Dis"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0263828","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T10:24:51Z","timestamp":1700216691000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0263828"}},"subtitle":[],"editor":[{"given":"Matias A.","family":"Avila","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,2,11]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0263828","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,11]]}}}