title: Marine sponge steroids as nuclear receptor ligands.
abstract: Nuclear receptors (NRs) are a large family of evolutionarily conserved and ligand-regulated transcription factors. The farnesoid X receptor (FXR) and the pregnane X receptor (PXR) are two bile-acid-activated receptors highly expressed in enterohepatic tissues essential for bile acids and xenobiotic metabolism. More than 1600 new steroidal structures have been isolated from marine organisms. Chemical, structural, and pharmacological characterization of sponge steroid libraries has allowed the identification of steroids that regulate FXR and PXR: selective FXR antagonists, FXR modulators, FXR antagonists endowed with PXR agonism, and selective PXR agonists. Selective FXR antagonists (theonellasterol) have proven effective in protecting against liver injury in models of cholestasis. Selective PXR agonists (natural and synthetic solomonsterols) have been effective in reducing nuclear factor (NF)-κB activity and intestinal inflammation. Identification of marine steroids endowed with dual FXR and PXR agonism-antagonism probably reflects the common identity of the unique ancestral precursor of these NRs. These findings pave the way to the development of novel FXR and PXR agonists and antagonists to target human diseases.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Nuova Facoltà di Medicina e Chirurgia, 06132 Perugia, Italy. fiorucci@unipg.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: D'Auria
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002757:Cholanes / Q000494:pharmacology*; D019143:Evolution, Molecular; D006801:Humans; D008024:Ligands; D016328:NF-kappa B / Q000378:metabolism; D011161:Porifera / Q000737:chemistry*; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013261:Sterols / Q000494:pharmacology*; D013463:Sulfuric Acid Esters / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002757:Cholanes; D008024:Ligands; D016328:NF-kappa B; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013261:Sterols; D013463:Sulfuric Acid Esters; D000099150:Receptor, Farnesoid X-Activated; C412852:7-hydroxytheonellasterol; C561233:cholan-2,3,24-tryl-2,3,24-trisulfate