Bile acids are the amphipathic terminal metabolites of hepatic cholesterol metabolism. In humans, cholic acid and chenodeoxycholic acid (CDCA; Chart 1) are the primary bile acids found in the enterohepatic circulation. These bile acids play important roles in the regulation of intestinal lipid absorption, bile flow, and biliary lipid secretion. 1, 2 Bile acids are synthesized in the liver and secreted into the intestine, where their physical properties facilitate the absorption of fats and vitamins through micelle formation. Cholesterol disposal from the liver is also dependent on the bile acid composition of the secreted bile. Impairments in the biosynthesis of bile acids, due to hereditary genetic defects, have been identified in children with severe cholestatic diseases and vitamin maladsorption. 3, 4 In addition to their role in the solubilization of fat and cholesterol, bile acids are signaling molecules that regulate the expression of genes involved in their biosynthesis and transport. In the liver, bile acids downregulate the transcription of the CYP7A gene, which encodes the enzyme that catalyzes the rate-limiting step in hepatic bile acid synthesis. 5 In the intestine, bile acids induce the expression of a bile acid-binding protein (IBABP), which is involved in the active transport of bile acids in the ileum. 6 Recently FXR (NR1H4), 7 an orphan member of the nuclear receptor gene family, was identified as a receptor for CDCA and other bile acids. 8-10 CDCA is found at micromolar concentrations in the liver and intestine, which matches the dose required to bind and activate FXR. A binding site has been identified in the promoter of the I-BABP gene, through which FXR regulates its transcription. 9, 11 FXR has also been shown to repress transcription of the CYP7A gene, 9, 10 although the mechanism may be complex since no FXR-binding site has been found in this gene promoter. 12 Analysis of the role of FXR in the regulation of bile acid and cholesterol homeostasis has been hampered by the lack of chemical tools to study the pharmacology ofthe receptor. CDCA, the most potent of the bile acids on FXR, is not well suited for this purpose, since it interacts with bile acid binding and transport proteins and is extensively metabolized in the intestine to form lithocholic acid. 13 The only known nonsteroidal FXR ligand is the retinoid TTNPB (Chart 1). 8, 14 However, TTNPB is only a weak FXR agonist (EC50> 1 μM) and