{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T07:53:29Z","timestamp":1789804409718,"version":"4.0.1"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["5R01AI143931-04"],"award-info":[{"award-number":["5R01AI143931-04"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Cyclophilins are a diverse family of peptidyl-prolyl isomerases (PPIases) of importance in a variety of essential cellular functions. We previously reported that the pan-cyclophilin inhibitor drug reconfilstat (CRV431) decreased disease in mice under the western-diet and carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) non-alcoholic steatohepatitis (NASH) model. CRV431 inhibits several cyclophilin isoforms, among which cyclophilin A (CypA) and B (CypB) are the most abundant. It is not known whether simultaneous inhibition of multiple cyclophilin family members is necessary for the observed therapeutic effects or if loss-of-function of one is sufficient. Identifying the responsible isoform(s) would enable future fine-tuning of drug treatments. Features of human liver fibrosis and complete NASH can be reliably replicated in mice by administration of intraperitoneal CCl<jats:sub>4<\/jats:sub> alone or CCl<jats:sub>4<\/jats:sub> in conjunction with high sugar, high cholesterol western diet, respectively. Here we show that while wild-type (WT) and Ppia-\/- CypA KO mice develop severe NASH disease features under these models, Ppib-\/- CypB KO mice do not, as measured by analysis of picrosirius red and hematoxylin &amp; eosin-stained liver sections and TNF\u03b1 immuno-stained liver sections. Cyclophilin inhibition is a promising and novel avenue of treatment for diet-induced NASH. In this study, mice without CypB, but not mice without CypA, were significantly protected from the development of the characteristic features of NASH. These data suggest that CypB is necessary for NASH disease progression. Further investigation is necessary to determine whether the specific role of CypB in the endoplasmic reticulum secretory pathway is of significance to its effect on NASH development.<\/jats:p>","DOI":"10.1371\/journal.pone.0298211","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T18:28:34Z","timestamp":1709317714000},"page":"e0298211","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mice lacking cyclophilin B, but not cyclophilin A, are protected from the development of NASH in a diet and chemical-induced model"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6092-6006","authenticated-orcid":true,"given":"Winston T.","family":"Stauffer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asha Z.","family":"Goodman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bobardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8762-6062","authenticated-orcid":true,"given":"Daren R.","family":"Ure","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Foster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6151-4764","authenticated-orcid":true,"given":"Philippe","family":"Gallay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,3,1]]},"reference":[{"issue":"10","key":"pone.0298211.ref001","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"R Loomba","year":"2021","journal-title":"Cell"},{"issue":"Suppl 1","key":"pone.0298211.ref002","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/liv.13299","article-title":"The epidemiology of non-alcoholic fatty liver disease","volume":"37","author":"S. Bellentani","year":"2017","journal-title":"Liver Int"},{"issue":"6","key":"pone.0298211.ref003","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nrgastro.2013.41","article-title":"Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis","volume":"10","author":"QM Anstee","year":"2013","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"20","key":"pone.0298211.ref004","doi-asserted-by":"crossref","DOI":"10.3390\/ijms20205037","article-title":"Development and Progression of Non-Alcoholic Fatty Liver Disease: The Role of Advanced Glycation End Products","volume":"20","author":"DH Fernando","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"4","key":"pone.0298211.ref005","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review","volume":"77","author":"ZM Younossi","year":"2023","journal-title":"Hepatology"},{"issue":"2","key":"pone.0298211.ref006","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1124\/jpet.119.261099","article-title":"A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models","volume":"371","author":"J Kuo","year":"2019","journal-title":"J Pharmacol Exp Ther"},{"key":"pone.0298211.ref007","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.3389\/fphar.2019.01129","article-title":"Cyclophilin Inhibitor NV556 Reduces Fibrosis and Hepatocellular Carcinoma Development in Mice With Non-Alcoholic Steatohepatitis","volume":"10","author":"J Kuo","year":"2019","journal-title":"Front Pharmacol"},{"issue":"11","key":"pone.0298211.ref008","doi-asserted-by":"crossref","DOI":"10.3390\/cells8111409","article-title":"Evaluation of NV556, a Novel Cyclophilin Inhibitor, as a Potential Antifibrotic Compound for Liver Fibrosis","volume":"8","author":"S Simon Serrano","year":"2019","journal-title":"Cells"},{"issue":"5","key":"pone.0298211.ref009","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1016\/j.jhep.2014.07.008","article-title":"Cyclophilin inhibition as potential therapy for liver diseases","volume":"61","author":"NV Naoumov","year":"2014","journal-title":"J Hepatol"},{"issue":"6206","key":"pone.0298211.ref010","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/337476a0","article-title":"Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins","volume":"337","author":"G Fischer","year":"1989","journal-title":"Nature"},{"issue":"6206","key":"pone.0298211.ref011","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/337473a0","article-title":"Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin","volume":"337","author":"N Takahashi","year":"1989","journal-title":"Nature"},{"issue":"10","key":"pone.0298211.ref012","doi-asserted-by":"crossref","first-page":"6030","DOI":"10.4049\/jimmunol.174.10.6030","article-title":"Cyclophilin A-deficient mice are resistant to immunosuppression by cyclosporine","volume":"174","author":"J Colgan","year":"2005","journal-title":"J Immunol"},{"issue":"10","key":"pone.0298211.ref013","doi-asserted-by":"crossref","first-page":"e888","DOI":"10.1038\/cddis.2013.410","article-title":"Cyclophilin A: a key player for human disease","volume":"4","author":"P Nigro","year":"2013","journal-title":"Cell Death Dis"},{"issue":"14","key":"pone.0298211.ref014","doi-asserted-by":"crossref","first-page":"7460","DOI":"10.1128\/JVI.00393-11","article-title":"Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner","volume":"85","author":"TL Foster","year":"2011","journal-title":"J Virol"},{"issue":"3","key":"pone.0298211.ref015","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1007\/s12026-011-8263-5","article-title":"Cyclophilin inhibitors: a novel class of promising host-targeting anti-HCV agents","volume":"52","author":"PA Gallay","year":"2012","journal-title":"Immunol Res"},{"issue":"6","key":"pone.0298211.ref016","doi-asserted-by":"crossref","first-page":"e0217433","DOI":"10.1371\/journal.pone.0217433","article-title":"The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice","volume":"14","author":"P Gallay","year":"2019","journal-title":"PLoS One"},{"issue":"9","key":"pone.0298211.ref017","doi-asserted-by":"crossref","first-page":"3931","DOI":"10.1073\/pnas.91.9.3931","article-title":"Cyclophilin B trafficking through the secretory pathway is altered by binding of cyclosporin A","volume":"91","author":"ER Price","year":"1994","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pone.0298211.ref018","article-title":"Cyclophilin B, a molecule chaperone, promotes adipogenesis in 3T3-L1 preadipocytes via AKT\/mTOR pathway","volume":"51","author":"JS Yoon","year":"2023","journal-title":"Int J Mol Med"},{"issue":"20","key":"pone.0298211.ref019","doi-asserted-by":"crossref","first-page":"4500","DOI":"10.1111\/febs.15249","article-title":"Inorganic polyphosphate controls cyclophilin B-mediated collagen folding in osteoblast-like cells","volume":"287","author":"ML Khong","year":"2020","journal-title":"FEBS J"},{"key":"pone.0298211.ref020","doi-asserted-by":"crossref","first-page":"595","DOI":"10.3389\/fphys.2020.00595","article-title":"Cyclophilin D: An Integrator of Mitochondrial Function","volume":"11","author":"G Amanakis","year":"2020","journal-title":"Front Physiol"},{"issue":"6341","key":"pone.0298211.ref021","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/353276a0","article-title":"Structure of human cyclophilin and its binding site for cyclosporin A determined by X-ray crystallography and NMR spectroscopy","volume":"353","author":"J Kallen","year":"1991","journal-title":"Nature"},{"issue":"4","key":"pone.0298211.ref022","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/0092-8674(91)90124-H","article-title":"Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes","volume":"66","author":"J Liu","year":"1991","journal-title":"Cell"},{"issue":"8","key":"pone.0298211.ref023","doi-asserted-by":"crossref","first-page":"e0134707","DOI":"10.1371\/journal.pone.0134707","article-title":"The Novel Cyclophilin Inhibitor CPI-431-32 Concurrently Blocks HCV and HIV-1 Infections via a Similar Mechanism of Action","volume":"10","author":"PA Gallay","year":"2015","journal-title":"PLoS One"},{"issue":"1 Suppl","key":"pone.0298211.ref024","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1177\/0023677215571192","article-title":"The carbon tetrachloride model in mice","volume":"49","author":"D Scholten","year":"2015","journal-title":"Lab Anim"},{"issue":"2","key":"pone.0298211.ref025","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.jhep.2018.03.011","article-title":"A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer","volume":"69","author":"T Tsuchida","year":"2018","journal-title":"J Hepatol"},{"issue":"48","key":"pone.0298211.ref026","doi-asserted-by":"crossref","first-page":"40293","DOI":"10.1074\/jbc.M506314200","article-title":"Naturally occurring capsid substitutions render HIV-1 cyclophilin A independent in human cells and TRIM-cyclophilin-resistant in Owl monkey cells","volume":"280","author":"U Chatterji","year":"2005","journal-title":"J Biol Chem"},{"issue":"3","key":"pone.0298211.ref027","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1021\/pr050276b","article-title":"Proteomic analysis of human immunodeficiency virus using liquid chromatography\/tandem mass spectrometry effectively distinguishes specific incorporated host proteins","volume":"5","author":"AC Saphire","year":"2006","journal-title":"J Proteome Res"},{"issue":"12","key":"pone.0298211.ref028","doi-asserted-by":"crossref","first-page":"e1000750","DOI":"10.1371\/journal.pgen.1000750","article-title":"Severe osteogenesis imperfecta in cyclophilin B-deficient mice","volume":"5","author":"JW Choi","year":"2009","journal-title":"PLoS Genet"},{"issue":"6","key":"pone.0298211.ref029","doi-asserted-by":"crossref","first-page":"e1004465","DOI":"10.1371\/journal.pgen.1004465","article-title":"Abnormal type I collagen post-translational modification and crosslinking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta","volume":"10","author":"WA Cabral","year":"2014","journal-title":"PLoS Genet"},{"issue":"18","key":"pone.0298211.ref030","doi-asserted-by":"crossref","first-page":"9501","DOI":"10.1074\/jbc.M115.699470","article-title":"Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen","volume":"291","author":"M Terajima","year":"2016","journal-title":"J Biol Chem"},{"issue":"3","key":"pone.0298211.ref031","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/hep.24127","article-title":"Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings","volume":"53","author":"EM Brunt","year":"2011","journal-title":"Hepatology"},{"issue":"4","key":"pone.0298211.ref032","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s40139-015-0093-z","article-title":"TNFalpha in liver fibrosis","volume":"3","author":"YM Yang","year":"2015","journal-title":"Curr Pathobiol Rep"},{"issue":"3","key":"pone.0298211.ref033","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/s41419-020-2411-6","article-title":"TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice","volume":"11","author":"F Wandrer","year":"2020","journal-title":"Cell Death Dis"},{"issue":"11","key":"pone.0298211.ref034","doi-asserted-by":"crossref","first-page":"e49670","DOI":"10.1371\/journal.pone.0049670","article-title":"Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liver failure and its neurological complications","volume":"7","author":"A Chastre","year":"2012","journal-title":"PLoS One"},{"issue":"6","key":"pone.0298211.ref035","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1056\/NEJMoa0907705","article-title":"Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding","volume":"362","author":"AM Barnes","year":"2010","journal-title":"N Engl J Med"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0298211","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T18:28:55Z","timestamp":1709317735000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0298211"}},"subtitle":[],"editor":[{"given":"Farhadul","family":"Islam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,3,1]]},"references-count":35,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0298211","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,1]]}}}