The novel compounds that activate farnesoid X receptor: The diversity of their effects on gene expression

Farnesoid X receptor (FXR) controls the expression of critical genes in bile acid and cholesterol homeostasis. To study FXR and to develop a regulator of cholesterol, some non-steroidal and steroidal ligands have been found in addition to endogenous ligands for FXR. In this study, we discovered five bile acid derivatives (methyl cholate, methyl deoxycholate, 5β-cholanic acid, 5β-cholanic acid-7α,12α-diol, and NIHS700) and two natural products (marchantin A and marchantin E) that activated FXR in the reporter assay. These compounds activated FXR to a high level comparable to the most potent endogenous bile acid, chenodeoxycholic acid, although it was not predicted from their structures; five of them were similar to the lower potency bile acids, and two were structurally much different from bile acids. The elevation levels of reporter gene expression by some of the screened compounds were varied in Cos-7, HepG2, HuH-7, and Caco-2 cells. These compounds also controlled the expression of genes regulated by FXR, and some of the compounds regulated these genes in a cell-type-specific and/or gene-selective fashion. Therefore, molecular design of the compounds can cause selective modulation of the expression of FXR target genes.