{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:00:54Z","timestamp":1791460854285,"version":"4.3.4"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T00:00:00Z","timestamp":1698624000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Aims<\/jats:title><jats:p>We have previously shown in a model of hepatic ischaemia\/reperfusion injury that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) restores reversion\u2010inducing\u2010cysteine\u2010rich protein with Kazal motifs (RECK), an inverse modulator of metalloproteases (MMPs) and inhibitor of the sheddases ADAM10 and ADAM17 involved in inflammation and fibrogenesis. Here, the effects of FXR agonists OCA and INT\u2010787 on hepatic levels of RECK, MMPs, ADAM10 and ADAM17 were compared in a diet\u2010induced ob\/ob mouse model of non\u2010alcoholic steatohepatitis (NASH).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Lep ob\/ob NASH mice fed a high\u2010fat diet (HFD) or control diet (CD) for 9 weeks (wks) were treated with OCA or INT\u2010787 0.05% dosed via HFD admixture (30\u2009mg\/kg\/day) or HFD for further 12 wks. Serum alanine transaminase (ALT) and inflammatory cytokines, liver RECK, MMP\u20102 and MMP\u20109 activity as well as ADAM10, ADAM17, collagen deposition (Sirius red), hepatic stellate cell activation (\u03b1\u2010SMA) and pCK<jats:sup>+<\/jats:sup> reactive biliary cells were quantified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Only INT\u2010787 significantly reduced serum ALT, IL\u20101\u03b2 and TGF\u2010\u03b2. A downregulation of RECK expression and protein levels observed in HFD groups (at 9 and 21 wks) was counteracted by both OCA and INT\u2010787. HFD induced a significant increase in liver MMP\u20102 and MMP\u20109; OCA administration reduced both MMP\u20102 and MMP\u20109 while INT\u2010787 markedly reduced MMP\u20102 expression. OCA and INT\u2010787 reduced both ADAM10 and ADAM17 expression and number of pCK<jats:sup>+<\/jats:sup> cells. INT\u2010787 was superior to OCA in decreasing collagen deposition and \u03b1\u2010SMA levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>INT\u2010787 is superior to OCA in controlling specific cell types and clinically relevant anti\u2010inflammatory and antifibrotic molecular mechanisms in NASH.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15767","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T06:26:26Z","timestamp":1698733586000},"page":"214-227","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["<scp>FXR<\/scp> agonists <scp>INT<\/scp>\u2010787 and <scp>OCA<\/scp> increase <scp>RECK<\/scp> and inhibit liver steatosis and inflammation in diet\u2010induced ob\/ob mouse model of <scp>NASH<\/scp>"],"prefix":"10.1111","volume":"44","author":[{"given":"Laura G.","family":"Di\u00a0Pasqua","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Therapeutics University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Cagna","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1312-7513","authenticated-orcid":false,"given":"Giuseppina","family":"Palladini","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics University of Pavia  Pavia Italy"},{"name":"Internal Medicine Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna C.","family":"Croce","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics Italian National Research Council (CNR)  Pavia Italy"},{"name":"Department of Biology and Biotechnology University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Cadamuro","sequence":"additional","affiliation":[{"name":"Department of Medicine (DIMED) University of Padua  Padua Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8538-6317","authenticated-orcid":false,"given":"Luca","family":"Fabris","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine (DMM) University of Padua  Padua Italy"},{"name":"Department of Internal Medicine, Liver Center and Section of Digestive Diseases Yale University  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Perlini","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics University of Pavia  Pavia Italy"},{"name":"Emergency Department Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Adorini","sequence":"additional","affiliation":[{"name":"Intercept Pharmaceuticals Inc.  Morristown New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2337-2897","authenticated-orcid":false,"given":"Andrea","family":"Ferrigno","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2464-6127","authenticated-orcid":false,"given":"Mariapia","family":"Vairetti","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Therapeutics University of Pavia  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,30]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0104-9"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11901-018-0425-7"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.07.034"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2022.111678"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.10.028"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0238543"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2015.01.004"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.084905"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-010-0345-y"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.779119"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8101226"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7836"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2009.00787.x"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.770740"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1006\/abio.1995.1126"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20130"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/803491"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-2675-7_2"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01126"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v24.i2.195"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-52736-y"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v12.i19.3044"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12621"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00767"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0041-1739455"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00062-3"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2021.1916465"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers6031220"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.22.13221"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00597-9"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.11.082"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2635"},{"key":"e_1_2_12_34_1","first-page":"1","article-title":"Matrix metalloproteinases as potential biomarkers and therapeutic targets in liver diseases","volume":"9","author":"Geervliet E","year":"2020","journal-title":"Cell"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-010-1296-0"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2011.05.005"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.2337\/db20-1228"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41522-023-00399-z"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2015.10.012"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0000000000000349"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00011.2021"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113380"},{"key":"e_1_2_12_43_1","first-page":"2","article-title":"Combined alcoholic and non\u2010alcoholic steatohepatitis","volume":"2","author":"Ntandja Wandji LC","year":"2020","journal-title":"JHEP Reports Innov Hepatol"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.15767","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T10:49:10Z","timestamp":1704278950000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/liv.15767"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,30]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1]]}},"alternative-id":["10.1111\/liv.15767"],"URL":"https:\/\/doi.org\/10.1111\/liv.15767","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,30]]},"assertion":[{"value":"2023-04-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}