{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T09:01:20Z","timestamp":1769245280892,"version":"3.49.0"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Digestive Health Foundation at Northwest"},{"name":"Digestive Health Foundation at Northwest"},{"name":"Pediatric Physician Scientist Research Award (PPSRA) at Ann & Robert H. Lurie Children\u2019s Hospital of Chicago"},{"DOI":"10.13039\/100017618","name":"Division of Diabetes, Endocrinology, and Metabolic Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017618","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005441","name":"Office of Budget, Finance and Award Management","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005441","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\">\n<jats:title>Background<\/jats:title>\n<jats:p>Increased intrahepatic bile acids cause endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) is activated to maintain homeostasis. UPR dysregulation, including the inositol-requiring enzyme 1\u03b1\/X-box protein 1 (IRE1\u03b1\/XBP1) pathway, is associated with adult liver diseases but has not been characterized in pediatric liver diseases. We evaluated hepatic UPR expression in pediatric cholestatic liver disease (CLD) explants and hypothesize that an inability to appropriately activate the hepatic IRE1\u03b1\/XBP1 pathway is associated with the pathogenesis of CLD.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We evaluated 34 human liver explants, including: pediatric CLD (Alagille, ALGS, and progressive familial intrahepatic cholestasis, PFIC), pediatric non-cholestatic liver disease controls (autoimmune hepatitis, AIH), adult CLD, and normal controls. We performed RNA-seq, quantitative PCR, and western blotting to measure expression differences of the hepatic UPR and other signaling pathways.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Pathway analysis demonstrated that the KEGG \u2018protein processing in ER\u2019 pathway was downregulated in pediatric CLD compared to normal controls. Pediatric CLD had decreased hepatic IRE1\u03b1\/XBP1 pathway gene expression and decreased protein expression of phosphorylated IRE1\u03b1 compared to normal controls. IRE1\u03b1\/XBP1 pathway gene expression was also decreased in pediatric CLD compared to AIH disease controls.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Pediatric CLD explants have decreased expression of the protective IRE1\u03b1\/XBP1 pathway and down-regulated KEGG protein processing in the ER pathways. IRE1\u03b1\/XBP1 pathway expression differences occur when compared to both normal and non-cholestatic disease controls. Attenuated expression of the IRE1\u03b1\/XBP1 pathway is associated with cholestatic diseases and may be a target for future therapeutics.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0279016","type":"journal-article","created":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T18:43:57Z","timestamp":1671129837000},"page":"e0279016","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Inositol-requiring enzyme 1\u03b1\/X-box protein 1 pathway expression is impaired in pediatric cholestatic liver disease explants"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0143-7450","authenticated-orcid":true,"given":"Alyssa","family":"Kriegermeier","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Hyon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"LeCuyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Hubchak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard M.","family":"Green","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,12,15]]},"reference":[{"issue":"2","key":"pone.0279016.ref001","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/ajt.15276","article-title":"OPTN\/SRTR 2017 Annual Data Report: Liver","volume":"19","author":"WR Kim","year":"2019","journal-title":"Am J Transplant"},{"issue":"1","key":"pone.0279016.ref002","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0378-4274(99)00113-7","article-title":"Activation of the promoters of genes associated with DNA damage, oxidative stress, ER stress and protein malfolding by the bile salt, deoxycholate","volume":"108","author":"H Bernstein","year":"1999","journal-title":"Toxicol Lett"},{"issue":"8","key":"pone.0279016.ref003","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nm.1853","article-title":"Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress","volume":"14","author":"IM Bochkis","year":"2008","journal-title":"Nat Med"},{"issue":"2","key":"pone.0279016.ref004","doi-asserted-by":"crossref","first-page":"G498","DOI":"10.1152\/ajpgi.00482.2007","article-title":"CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury","volume":"294","author":"N Tamaki","year":"2008","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"2","key":"pone.0279016.ref005","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.toxlet.2006.06.006","article-title":"Involvement of endoplasmic reticulum in glycochenodeoxycholic acid-induced apoptosis in rat hepatocytes","volume":"166","author":"S Tsuchiya","year":"2006","journal-title":"Toxicol Lett"},{"issue":"46","key":"pone.0279016.ref006","doi-asserted-by":"crossref","first-page":"31807","DOI":"10.1074\/jbc.M109.017970","article-title":"Homocysteine supplementation attenuates the unfolded protein response in a murine nutritional model of steatohepatitis","volume":"284","author":"AS Henkel","year":"2009","journal-title":"The Journal of biological chemistry"},{"issue":"5","key":"pone.0279016.ref007","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1016\/S0016-5085(03)00276-2","article-title":"Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice","volume":"124","author":"C Ji","year":"2003","journal-title":"Gastroenterology"},{"issue":"2","key":"pone.0279016.ref008","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1053\/j.gastro.2007.10.039","article-title":"Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease","volume":"134","author":"P Puri","year":"2008","journal-title":"Gastroenterology"},{"issue":"15","key":"pone.0279016.ref009","doi-asserted-by":"crossref","first-page":"7453","DOI":"10.1128\/JVI.76.15.7453-7459.2002","article-title":"Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway","volume":"76","author":"KD Tardif","year":"2002","journal-title":"J Virol"},{"issue":"2","key":"pone.0279016.ref010","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.molcel.2017.06.017","article-title":"The Unfolded Protein Response and Cell Fate Control","volume":"69","author":"C Hetz","year":"2018","journal-title":"Mol Cell"},{"issue":"1","key":"pone.0279016.ref011","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/hep.29815","article-title":"Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice","volume":"68","author":"X Liu","year":"2018","journal-title":"Hepatology (Baltimore, Md)."},{"issue":"3","key":"pone.0279016.ref012","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1194\/jlr.M071266","article-title":"Hepatic deletion of X-box binding protein 1 impairs bile acid metabolism in mice","volume":"58","author":"X Liu","year":"2017","journal-title":"J Lipid Res"},{"issue":"2","key":"pone.0279016.ref013","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.jcmgh.2016.11.006","article-title":"Endoplasmic Reticulum Stress Regulates Hepatic Bile Acid Metabolism in Mice","volume":"3","author":"AS Henkel","year":"2017","journal-title":"Cell Mol Gastroenterol Hepatol"},{"issue":"50","key":"pone.0279016.ref014","doi-asserted-by":"crossref","first-page":"30142","DOI":"10.1074\/jbc.M115.676239","article-title":"Hepatic Xbp1 Gene Deletion Promotes Endoplasmic Reticulum Stress-induced Liver Injury and Apoptosis","volume":"290","author":"S Olivares","year":"2015","journal-title":"J Biol Chem"},{"key":"pone.0279016.ref015","article-title":"Hepatic X-box binding protein 1 and unfolded protein response is impaired in weanling mice with resultant hepatic injury","author":"A Kriegermeier","year":"2021","journal-title":"Hepatology"},{"key":"pone.0279016.ref016","first-page":"10","article-title":"Cutadapt Removes Adapter Sequences From High-Throughput Sequencing Reads","volume":"17","author":"M. Martin","year":"2011","journal-title":"EMBnetjournal"},{"issue":"1","key":"pone.0279016.ref017","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"A Dobin","year":"2013","journal-title":"Bioinformatics"},{"issue":"2","key":"pone.0279016.ref018","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2014a Python framework to work with high-throughput sequencing data","volume":"31","author":"S Anders","year":"2015","journal-title":"Bioinformatics"},{"issue":"12","key":"pone.0279016.ref019","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"MI Love","year":"2014","journal-title":"Genome Biol"},{"key":"pone.0279016.ref020","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1007\/978-1-4419-9863-7_1215","volume-title":"Encyclopedia of Systems Biology.","author":"W. Haynes","year":"2013"},{"issue":"1","key":"pone.0279016.ref021","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Y Zhou","year":"2019","journal-title":"Nat Commun"},{"issue":"2","key":"pone.0279016.ref022","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/hep.510240201","article-title":"An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group","volume":"24","author":"P Bedossa","year":"1996","journal-title":"Hepatology"},{"issue":"12","key":"pone.0279016.ref023","doi-asserted-by":"crossref","first-page":"G965","DOI":"10.1152\/ajpgi.00132.2015","article-title":"Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat\/sugar diet","volume":"309","author":"X Liu","year":"2015","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"pone.0279016.ref024","doi-asserted-by":"crossref","DOI":"10.1002\/hep.32562","article-title":"Endoplasmic Reticulum Stress in Liver Diseases","author":"A Ajoolabady","year":"2022","journal-title":"Hepatology"},{"issue":"530","key":"pone.0279016.ref025","article-title":"IRE1alpha prevents hepatic steatosis by processing and promoting the degradation of select microRNAs","volume":"11","author":"JM Wang","year":"2018","journal-title":"Sci Signal"},{"issue":"4","key":"pone.0279016.ref026","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1053\/j.gastro.2020.06.031","article-title":"IRE1A Stimulates Hepatocyte-Derived Extracellular Vesicles That Promote Inflammation in Mice With Steatohepatitis","volume":"159","author":"D Dasgupta","year":"2020","journal-title":"Gastroenterology"},{"key":"pone.0279016.ref027","article-title":"A Fibrosis-Independent Hepatic Transcriptomic Signature Identifies Novel Drivers of Disease Progression in Primary Sclerosing Cholangitis","author":"Y Gindin","year":"2020","journal-title":"Hepatology"},{"issue":"21","key":"pone.0279016.ref028","doi-asserted-by":"crossref","first-page":"7448","DOI":"10.1128\/MCB.23.21.7448-7459.2003","article-title":"XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response","volume":"23","author":"AH Lee","year":"2003","journal-title":"Mol Cell Biol"},{"issue":"11","key":"pone.0279016.ref029","doi-asserted-by":"crossref","first-page":"7969","DOI":"10.1074\/jbc.M111.311290","article-title":"ERdj4 protein is a soluble endoplasmic reticulum (ER) DnaJ family protein that interacts with ER-associated degradation machinery","volume":"287","author":"CW Lai","year":"2012","journal-title":"J Biol Chem"},{"issue":"5","key":"pone.0279016.ref030","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1093\/embo-reports\/kve084","article-title":"A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation","volume":"2","author":"N Hosokawa","year":"2001","journal-title":"EMBO Rep"},{"issue":"4","key":"pone.0279016.ref031","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1055\/s-2007-991513","article-title":"Endoplasmic reticulum stress and liver injury","volume":"27","author":"N Kaplowitz","year":"2007","journal-title":"Semin Liver Dis"},{"issue":"1","key":"pone.0279016.ref032","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.livres.2019.01.002","article-title":"Endoplasmic reticulum stress and liver diseases","volume":"3","author":"X Liu","year":"2019","journal-title":"Liver Res"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0279016","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T18:44:32Z","timestamp":1671129872000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0279016"}},"subtitle":[],"editor":[{"given":"Heather","family":"Francis","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,12,15]]},"references-count":32,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12,15]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0279016","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,15]]}}}