Recent studies reveal that
bile acids are signalling molecules that activate several
nuclear receptors and regulate many physiological pathways and processes to maintain
bile acid and
cholesterol homeostasis. Analysis of orphan receptor expression patterns in enterohepatic tissues identified
bile acids as
ligands for farnesoid X receptor (FXR). The primary
bile acid chenodeoxycholic acid (CDCA) was shown to be the most potent FXR
ligand in vitro at an EC50 of 10-50 microM. FXR can also be activated by the secondary
bile acids lithocholic acid (LCA) and
deoxycholic acid (DCA). Upon activation FXR heterodimerises with 9-cis retinoic X receptor (RXR) and regulates a cohort of genes involved in
cholesterol catabolism and
bile acids biosynthesis. Thus
bile acid-activated FXR directly induces expression of Small Heterodimer Partner (SHP), a
nuclear receptor that suppresses
bile acid biosynthesis down-regulates the Na+
taurocholate cotransport
peptide (NTCP), a pump depicted to transport
bile acids from the lumen into hepatocyte, and induces expression of
bile salt export pump (BSEP), the principal
bile acid efflux transporter in the liver. As demonstrated by the Fxr null mice, FXR defends the liver against
cholestasis. The 6-ethyl derivative of CDCA (6-ECDCA) is approximately 100 fold more potent than CDCA in activating FXR in vitro. In vivo administration of
6-ECDCA protects against
cholestasis induced by
estrogen and LCA in rats providing evidence that development of potent FXR agonists might represent a new approach for the treatment of cholestastic disorders.