*7.1. Transcriptional Modulators*

FXR is the major ligand-activated transcription factor controlling BSEP expression, which makes it a possible target for therapeutic intervention. Furthermore, 6α-ethyl-CDCA (obeticholic acid, OCA), a derivative of the primary human bile acid CDCA and an FXR agonist, was approved by the FDA for the treatment of primary biliary cholangitis (PBC) either in monotherapy or in combination with UDCA in adults, depending on UDCA responsivity and tolerability [120]. OCA's 100-fold higher FXR-activating potential (as compared to the natural ligand CDCA) formed the basis for advocating it as a novel therapeutic treatment strategy for PBC [121]. Its long-term efficacy and safety profile were reported recently [122]. OCA was also introduced for the treatment of non-alcoholic steatohepatitis (NASH), whereby the interim analysis from a phase 3 trial demonstrated clinical improvement and partial reversal of histopathological features [123]. Several other steroidal and non-steroidal FXR agonists, such as EDP-305 and tropifexor (LJN4524), are currently being investigated in a clinical setting for the treatment of NASH [124].

Garzel and co-workers evaluated the effects of 30 BSEP inhibitors on BSEP expression and FXR activation in human primary hepatocytes to understand the underlying mechanisms of drug-induced liver injury (DILI) [125]. Among five potent transcriptional repressors, lopinavir and troglitazone were shown to mediate their effects by reducing the FXR activity. The latter drug was previously withdrawn from the market because of DILI [125]. A number of natural FXR agonists or antagonists were reported to modulate FXR activity in a variety of model systems, as reviewed in detail by Hiebl et al. [126]. A natural product, geniposide, was reported to modulate the expression of BSEP via the FXR, as well as via the Nrf2 signaling pathways [127]. On the other hand, 9-cis retinoic acid (9cRA) is an RXR agonist, which when co-administered with CDCA, represses FXR/RXR-mediated expression of BSEP, thus exerting an opposite effects on BSEP transcription [128].
