PMID- 33314176 OWN - NLM STAT- MEDLINE DCOM- 20220104 LR - 20220716 IS - 1527-3350 (Electronic) IS - 0270-9139 (Print) IS - 0270-9139 (Linking) VI - 74 IP - 1 DP - 2021 Jul TI - Farnesoid X Receptor Activation Impairs Liver Progenitor Cell-Mediated Liver Regeneration via the PTEN-PI3K-AKT-mTOR Axis in Zebrafish. PG - 397-410 LID - 10.1002/hep.31679 [doi] AB - 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. CI - (c) 2020 by the American Association for the Study of Liver Diseases. FAU - Jung, Kyounghwa AU - Jung K AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA. FAU - Kim, Minwook AU - Kim M AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA. FAU - So, Juhoon AU - So J AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA. FAU - Lee, Seung-Hoon AU - Lee SH AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA. FAU - Ko, Sungjin AU - Ko S AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA. AD - Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA. FAU - Shin, Donghun AU - Shin D AD - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA. LA - eng GR - R01 DK101426/DK/NIDDK NIH HHS/United States GR - R01 DK116993/DK/NIDDK NIH HHS/United States GR - P30 DK120531/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210615 PL - United States TA - Hepatology JT - Hepatology (Baltimore, Md.) JID - 8302946 RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Receptors, Cytoplasmic and Nuclear) RN - 0 (Zebrafish Proteins) RN - 0C5V0MRU6P (farnesoid X-activated receptor) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (mTOR protein, zebrafish) RN - EC 3.1.3.16 (Phosphoprotein Phosphatases) RN - EC 3.1.3.16 (Ptena protein, zebrafish) RN - EC 3.1.3.16 (Ptenb protein, zebrafish) SB - IM MH - Animals MH - Animals, Genetically Modified MH - Biliary Tract/cytology MH - Cell Differentiation/*drug effects MH - Cell Proliferation MH - Drug Evaluation, Preclinical MH - Epithelial Cells/drug effects/physiology MH - Hepatocytes/drug effects/physiology MH - Liver/drug effects/physiology MH - Liver Regeneration/*drug effects MH - Mutation MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphoinositide-3 Kinase Inhibitors MH - Phosphoprotein Phosphatases/antagonists & inhibitors/genetics/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Receptors, Cytoplasmic and Nuclear/*agonists/metabolism MH - Stem Cells/*drug effects/physiology MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism MH - Zebrafish MH - Zebrafish Proteins/antagonists & inhibitors/genetics/metabolism PMC - PMC8605479 MID - NIHMS1754431 COIS- Potential conflict of interest: Nothing to report. EDAT- 2020/12/15 06:00 MHDA- 2022/01/05 06:00 PMCR- 2022/07/01 CRDT- 2020/12/14 11:07 PHST- 2020/11/15 00:00 [revised] PHST- 2020/07/05 00:00 [received] PHST- 2020/11/29 00:00 [accepted] PHST- 2020/12/15 06:00 [pubmed] PHST- 2022/01/05 06:00 [medline] PHST- 2020/12/14 11:07 [entrez] PHST- 2022/07/01 00:00 [pmc-release] AID - 10.1002/hep.31679 [doi] PST - ppublish SO - Hepatology. 2021 Jul;74(1):397-410. doi: 10.1002/hep.31679. Epub 2021 Jun 15.