Farnesoid X Receptor Activation Impairs Liver Progenitor Cell–Mediated Liver Regeneration via the PTEN‐PI3K‐AKT‐mTOR Axis in Zebrafish

Background and Aims Following mild liver injury, pre‐existing hepatocytes replicate. However, if hepatocyte proliferation is compromised, such as in chronic liver diseases, biliary epithelial cells (BECs) contribute to hepatocytes through liver progenitor cells (LPCs), thereby restoring hepatic mass and function. Recently, augmenting innate BEC‐driven liver regeneration has garnered attention as an alternative to liver transplantation, the only reliable treatment for patients with end‐stage liver diseases. Despite this attention, the molecular basis of BEC‐driven liver regeneration remains poorly understood. Approach and Results By performing a chemical screen with the zebrafish hepatocyte ablation model, in which BECs robustly contribute to hepatocytes, we identified farnesoid X receptor (FXR) agonists as inhibitors of BEC‐driven liver regeneration. Here we show that FXR activation blocks the process through the FXR‐PTEN (phosphatase and tensin homolog)–PI3K (phosphoinositide 3‐kinase)–AKT‐mTOR (mammalian target of rapamycin) axis. We found that FXR activation blocked LPC‐to‐hepatocyte differentiation, but not BEC‐to‐LPC dedifferentiation. FXR activation also suppressed LPC proliferation and increased its death. These defects were rescued by suppressing PTEN activity with its chemical inhibitor and ptena / b mutants, indicating PTEN as a critical downstream mediator of FXR signaling in BEC‐driven liver regeneration. Consistent with the role of PTEN in inhibiting the PI3K‐AKT‐mTOR pathway, FXR activation reduced the expression of pS6, a marker of mTORC1 activation, in LPCs of regenerating livers. Importantly, suppressing PI3K and mTORC1 activities with their chemical inhibitors blocked BEC‐driven liver regeneration, as did FXR activation. Conclusions FXR activation impairs BEC‐driven liver regeneration by enhancing PTEN activity; the PI3K‐AKT‐mTOR pathway controls the regeneration process. Given the clinical trials and use of FXR agonists for multiple liver diseases due to their beneficial effects on steatosis and fibrosis, the detrimental effects of FXR activation on LPCs suggest a rather personalized use of the agonists in the clinic.