Characterizing a Novel Ligand for the Farnesoid X Receptor using Transgenic Zebrafish

Nuclear receptors (NRs) are ligand activated transcription factors that are involved in variety of processes, such as metabolism, development, and reproduction. The farnesoid x receptor (FXR) is a NR that is involved in maintaining lipid homeostasis in the liver. When FXR is downregulated in the liver, diseases such as fatty liver disease can arise. Using the ligand-trap system in zebrafish, a novel ligand for FXR, 8215 Ethyl, was identified. This ligand was characterized and it was discovered that 8215 Ethyl induces FXR expression robustly and selectively in the liver at non-toxic concentrations. 8215 Ethyl is also able to induce activation of the NRs PPARγ and RORγ in zebrafish. FXR, PPARγ, and RORγ are regulated by 8215 Ethyl through the direct binding of the ligand to the ligand binding domains of these NRs. These findings indicate that 8215 Ethyl may have therapeutic potential to treat diseases associated with downregulation of FXR.M.Sc