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)-kB 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.
Marine sponge steroids as nuclear receptor ligands
BIFULCO, Giuseppe;
2012-01-01
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)-kB 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
