FXR activation impairs liver progenitor cell‐driven liver regeneration by enhancing PTEN‐dependent inhibition of AKT‐mTOR axis
Authors: Ko Sungjin , Jung Kyounghwa , Russell Jacquelyn O. , Kim Min‐wook , So Juhoon , Monga Satdarshan Pal , Shin Donghun 
Published: June 2021

Liver progenitor cells (LPCs) are activated by liver injury and their expansion correlates with disease severity. However, the differentiation of this population into hepatocytes occurs only in extreme situations, when hepatocytes fail to proliferate or senescence, to restore hepatic mass and function. Furthermore, expanding LPCs, if unable to differentiate, can secrete pro‐inflammatory and pro‐fibrogenic cytokines and thus not only fail to contribute to recovery but may, in fact, contribute to ongoing injury in the diseased livers. Recently, promoting LPC‐driven liver regeneration has garnered attention as an alternative to liver transplantation, the only reliable treatment for patients with end‐stage liver diseases. However, the molecular mechanisms of LPC‐driven repair are largely unknown. Farnesoid X receptor (FXR) is a bile acid receptor and biological sensor for the regulation of systemic bile acid homeostasis. Activation of FXR, using synthetic agonists, has shown beneficial effects on various liver diseases, including metabolic disorders, liver regeneration, and liver cancer. Currently, obeticholic acid (OCA, selective FXR agonist) is in phase II/III clinical trials for several liver diseases, such as primary biliary cholangitis, alcoholic hepatitis, and non‐alcoholic steatohepatitis (NASH). However, no studies have addressed the role of FXR signaling in LPC‐driven liver regeneration. To investigate the effect of FXR activation on LPC‐driven liver regeneration, we utilized a zebrafish liver injury model in which the robust transition of biliary epithelial cells (BECs) into hepatocytes occurs upon pharmarcogenetic pan‐hepatocyte ablation. Intriguingly, treating hepatocyte‐ablated zebrafish larvae with the FXR agonist, GW4064, impaired LPC‐driven liver regeneration by: (1) repressing differentiation of LPCs to either hepatocytes or BECs, (2) reducing proliferation of LPC‐derived cells, and (3) inducing death of LPC–derived cells. Notably, pten expression was significantly enhanced in regenerating livers by GW4064 treatment. Intriguingly, the pharmacologic inhibition of PTEN downstream factors, PI3K, AKT, mTOR and BCL2, resulted in similar regeneration defects as observed by FXR activation. Moreover, regeneration defects observed in GW4064‐treated larvae were partially rescued in larvae co‐treated with a PTEN inhibitor and in ptena/b heterozygous mutant fish, suggesting PTEN as a key downstream mediator of FXR signaling in LPC‐driven liver regeneration. Lastly, fxr mutant fish exhibited enhanced LPC‐to‐hepatocyte differentiation compared with their wild‐type sibling fish. Collectively, our study reveals novel molecular mechanisms by which FXR activation impairs LPC‐driven liver regeneration partly by enhancing pten expression, which inhibits the AKT‐mTOR‐BCL2 axis. Thus, our results provide insights into the molecular mechanisms regulating LPC‐driven liver regeneration and lay the foundation for developing therapeutics to promote LPC differentiation in patients with advanced liver diseases.Support or Funding InformationNIH grants to D.S. (DK101426) and S.P.M. (DK62277, DK100287, CA204586). Endowed Chair for Experimental Pathology to S.P.M.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.