Previous studies have demonstrated a dramatic induction of inflammatory gene expression in livers from mice fed a high fat, high cholesterol diet containing cholate after 3-5 weeks. To determine the contribution of cholate in mediating these inductions, C57BL/6 mice were fed a chow diet supplemented with increasing concentrations of cholic acid (CA) for 5 days. A dose dependent induction in the hepatic levels of TNF, VCAM-1, ICAM-1 and SAA-2 mRNA were observed. As positive controls, a dose dependent repression of cholesterol 7-hydroxylase (CYP7A1) and a dose dependent induction of SHP expression were also observed suggesting that FXR was activated. In addition, ICAM-1 and SHP mRNA levels were also induced in primary human hepatocytes when treated with chenodeoxycholic acid (CDCA), or GW4064, a FXR-selective agonist. The involvement of FXR in CA induced inflammatory gene expression was further investigated in the human hepatic cell line, HepG2. Both ICAM-1 and SHP expression were induced in a dose- and time- dependent manner by treatment with the FXR-selective agonist GW4064. Moreover, the induction of ICAM-1 by GW4064 was inhibited by the FXR antagonist guggulsterone or with transfection of FXR siRNA. Finally, the activity of FXR was mapped to a RARE site containing an imbedded FXRE on the human ICAM-1 promoter and FXR and RXR were demonstrated to bind to this site. Finally, FXR-mediated activation of ICAM-1 could be further enhanced by TNF co-treatment in hepatocytes suggesting a potential cooperation between cytokine and bile acid signaling pathways during hepatic inflammatory events.