title: Decoding the role of the nuclear receptor SHP in regulating hepatic stellate cells and liver fibrogenesis.
abstract: The small heterodimer partner (SHP) is an orphan nuclear receptor that lacks the DNA binding domain while conserves a putative ligand-binding site, thought that endogenous ligands for this receptor are unknown. 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 (EC50: 9 μM), attenuated HSCs trans-differentiation and ECM deposition in vitro, while in mice rendered cirrhotic by carbon tetrachloride (CCl4) or α-naphthyl-isothiocyanate (ANIT), protected against development of liver fibrosis as measured by morphometric analysis and expression of α-SMA and α1-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.
authors.affiliation: Dipartimento di Medicina, Università degli Studi di Perugia, Nuova Facoltà di Medicina e Chirurgia, Sant'Andrea delle Fratte, Perugia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.affiliation: Dipartimento di Scienze Chirurgiche e Biomediche, Università degli Studi di Perugia Nuova Facoltà di Medicina e Chirurgia, Sant' Andrea delle Fratte, Perugia, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Carino
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Napoli, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Masullo
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II, Napoli, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.affiliation: Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.affiliation: Dipartimento di Scienze Chirurgiche e Biomediche, Università degli Studi di Perugia Nuova Facoltà di Medicina e Chirurgia, Sant' Andrea delle Fratte, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D015058:1-Naphthylisothiocyanate; D002251:Carbon Tetrachloride