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Previous studies have determined that SHP activation protects against development of liver fibrosis a process driven by trans-differentiation and activation of hepatic stellate cells (HSCs), a miofibroblast like cell type, involved in extracellular matrix (ECM) deposition. To dissect signals involved in this activity we generated SHP-overexpressing human and rat HSCs. Forced expression of SHP in HSC-T6 altered the expression of 574 genes. By pathway and functional enrichment analyses we detected a cluster of 46 differentially expressed genes involved in HSCs trans-differentiation. Using a isoxazole scaffold we designed and synthesized a series of SHP agonists. The most potent member of this group, ISO-COOH (EC<jats:sub>50<\/jats:sub>: 9\u2009\u03bcM), attenuated HSCs trans-differentiation and ECM deposition <jats:italic>in vitro<\/jats:italic>, while in mice rendered cirrhotic by carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) or \u03b1-naphthyl-isothiocyanate (ANIT), protected against development of liver fibrosis as measured by morphometric analysis and expression of \u03b1-SMA and \u03b11-collagen mRNAs. In aggregate, present results identify SHP as a counter-regulatory signal for HSCs transactivation and describe a novel class of SHP agonists endowed with anti-fibrotic activity.<\/jats:p>","DOI":"10.1038\/srep41055","type":"journal-article","created":{"date-parts":[[2017,1,24]],"date-time":"2017-01-24T11:27:41Z","timestamp":1485257261000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Decoding the role of the nuclear receptor SHP in regulating hepatic stellate cells and liver fibrogenesis"],"prefix":"10.1038","volume":"7","author":[{"given":"Sabrina","family":"Cipriani","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana","family":"Carino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dario","family":"Masullo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Zampella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonora","family":"Distrutti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Fiorucci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,1,24]]},"reference":[{"key":"BFsrep41055_CR1","doi-asserted-by":"publisher","first-page":"486","DOI":"10.2174\/156802612799436641","volume":"12","author":"M Pawlak","year":"2012","unstructured":"Pawlak, M., Lefebvre, P. & Staels, B. 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