Disruption of TFG-beta SMAD3 pathway by the nuclear receptor SHP mediates the antifibrotic activities of BAR704, a novel highly selective FXR ligand

Liver fibrosis, a major health concern worldwide, results from abnormal collagen deposition by activated hepatic stellate cells (HSCs) in an injured liver. The farnesoid-x-receptor (FXR) is a bile acid sensor that counteracts HSCs transdifferentiation. While targeting FXR holds promise, 6-ethyl-CDCA known as obeticholic acid, the first in class of FXR ligands, causes side effects, partially because the lack of selectivity toward GPBAR1, a putative itching receptor. Here, we describe the 3-deoxy-6-ethyl derivative of CDCA, BAR704, as a highly selective steroidal FXR agonist.