FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity

Background & Aims: Bile acids are essential for bile formation and Intestinal absorption of lipids and fat-soluble vitamins. However, the intrinsic toxicity of hydrophobic bile acids demands a tight control of their intracellular concentrations. Bile acids are ligands for the farnesoid X receptor (FXR) that regulates the expression of genes controlling bile acid synthesis and transport. The human uridine 5'-diphosphate-glucuronosyltransferase 21314 (UGT2B4) converts hydrophobic bile acids into more hydrophilic glucuronide derivatives. In this study, we identify UGT2B4 as an FXR target gene. Methods. Human hepatocytes or hepatoblastoma HepG2 cells were treated with chenodeoxycholic acid or the synthetic FXR agonist GW4064, and the levels of UGT2134 messenger RNA, protein, and activity were determined by using real-time polymerase chain reaction, Western blot, and glucuronidation assays. Results: Treatment of hepatocytes and HepG2 cells with FXR agonists resulted in an increase of UGT2134 messenger R A, protein, and activity. A bile acid response element in the UGT2134 promoter (B4-BARE) to which FXR, but not retinoid X receptor, binds, was identified by site-directed mutagenesis, electromobility shift, and chromatin 1 m m uno precipitation assays. Retinoid X receptor activation abolished the induction of UGT2B4 expression and inhibited binding of FXR to the B4-BARE, suggesting that retinoid X receptor modulates FXR target gene activation. Overexpression of UGT2134 in HepG2 cells resulted in the attenuation of bile acid induction of the FXR target gene small heterodimeric partner. Conclusions: These data suggest that UGT2134 gene induction by bile acids contributes to a feed-forward reduction of bile acid toxicity and a decrease of the activity of these biological FXR activators.