{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:33:54Z","timestamp":1791588834229,"version":"4.3.4"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T00:00:00Z","timestamp":1665532800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/ http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aim:<\/jats:title>\n            <jats:p>Drug\u2010induced liver injury (DILI) is a common disorder that involves both direct liver cell toxicity and immune activation. The bile acid receptor, G\u2010protein\u2010coupled bile acid receptor 1 (GPBAR1; Takeda G\u2010protein\u2010coupled receptor 5 [TGR5]), and cysteinyl leukotriene receptor (CYSLTR) 1 are G\u2010protein\u2010coupled receptors activated by bile acids and leukotrienes, exerting opposite effects on cell\u2010to\u2010cell adhesion, inflammation, and immune cell activation. To investigate whether GPBAR1 and CYSLTR1 mutually interact in the development of DILI, we developed an orally active small molecule, CHIN117, that functions as a GPBAR1 agonist and CYSLTR1 antagonist.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results:<\/jats:title>\n            <jats:p>RNA\u2010sequencing analysis of liver explants showed that acetaminophen (APAP) intoxication positively modulates the leukotriene pathway, CYSLTR1, 5\u2010lipoxygenase, and 5\u2010lipoxygenase activating protein, whereas GPBAR1 gene expression was unchanged. In mice, acute liver injury induced by orally dosing APAP (500\u2009mg\/kg) was severely exacerbated by Gpbar1 gene ablation and attenuated by anti\u2010Cysltr1 small interfering RNA pretreatment. Therapeutic dosing of wild\u2010type mice with CHIN117 reversed the liver damage caused by APAP and modulated up to 1300 genes, including 38 chemokines and receptors, that were not shared by dosing mice with a selective GPBAR1 agonist or CYSLTR1 antagonist. Coexpression of the two receptors was detected in liver sinusoidal endothelial cells (LSECs), monocytes, and Kupffer cells, whereas combinatorial modulation of CYSLTR1 and GPBAR1 potently reversed LSEC\/monocyte interactions. CHIN117 reversed liver damage and liver fibrosis in mice administered CCl<jats:sub>4<\/jats:sub>.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>By genetic and pharmacological approaches, we demonstrated that GPBAR1 and CYSLTR1 mutually interact in the development of DILI. A combinatorial approach designed to activate GPBAR1 while inhibiting CYSLTR1 reverses liver injury in models of DILI.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32787","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T09:58:26Z","timestamp":1663235906000},"page":"26-44","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":26,"title":["Combinatorial targeting of G\u2010protein\u2010coupled bile acid receptor 1 and cysteinyl leukotriene receptor 1 reveals a mechanistic role for bile acids and leukotrienes in drug\u2010induced liver injury"],"prefix":"10.1097","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2995-6896","authenticated-orcid":false,"given":"Michele","family":"Biagioli","sequence":"first","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 di Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Marchian\u00f2","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 di Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"di Giorgio","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 di Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalinda","family":"Roselli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Universit\u00e0 di Napoli \u201cFederico II\u201d, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Bordoni","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 di Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachele","family":"Bellini","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 di Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3025-5157","authenticated-orcid":false,"given":"Bianca","family":"Fiorillo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Universit\u00e0 di Napoli \u201cFederico II\u201d, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Sepe","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Universit\u00e0 di Napoli \u201cFederico II\u201d, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Catalanotti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Universit\u00e0 di Napoli \u201cFederico II\u201d, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Cassiano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Universit\u00e0 di Napoli \u201cFederico II\u201d, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Chiara","family":"Monti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Distrutti","sequence":"additional","affiliation":[{"name":"SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Zampella","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Universit\u00e0 di Napoli \u201cFederico II\u201d, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3816-4222","authenticated-orcid":false,"given":"Stefano","family":"Fiorucci","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 di Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"issue":"1","key":"hep32787-bib-0001-20250824","article-title":"Drug\u2010induced liver injury","volume":"5","year":"2019","journal-title":"Nat Rev Dis Prim"},{"issue":"3","key":"hep32787-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.cld.2007.06.006","article-title":"Acetaminophen hepatotoxicity","volume":"11","year":"2007","journal-title":"Clin Liver Dis"},{"issue":"6","key":"hep32787-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1111\/apt.13943","article-title":"Acute liver failure 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