PUBLICATION
PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish
- Authors
- Kim, M., So, J., Shin, D.
- ID
- ZDB-PUB-231026-56
- Date
- 2023
- Source
- Scientific Reports 13: 1831218312 (Journal)
- Registered Authors
- Shin, Donghun, So, Juhoon
- Keywords
- none
- Datasets
- GEO:GSE226923
- MeSH Terms
-
- Animals
- Cell Proliferation
- Hepatocytes/metabolism
- Humans
- Liver/metabolism
- Liver Diseases*/metabolism
- Liver Regeneration/physiology
- PPAR alpha/metabolism
- Stem Cells/metabolism
- Zebrafish*/genetics
- beta Catenin/metabolism
- PubMed
- 37880271 Full text @ Sci. Rep.
Citation
Kim, M., So, J., Shin, D. (2023) PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish. Scientific Reports. 13:1831218312.
Abstract
Despite the robust regenerative capacity of the liver, prolonged and severe liver damage impairs liver regeneration, leading to liver failure. Since the liver co-opts the differentiation of liver progenitor cells (LPCs) into hepatocytes to restore functional hepatocytes, augmenting LPC-mediated liver regeneration may be beneficial to patients with chronic liver diseases. However, the molecular mechanisms underlying LPC-to-hepatocyte differentiation have remained largely unknown. Using the zebrafish model of LPC-mediated liver regeneration, Tg(fabp10a:pt-β-catenin), we present that peroxisome proliferator-activated receptor-alpha (PPARα) activation augments LPC-to-hepatocyte differentiation. We found that treating Tg(fabp10a:pt-β-catenin) larvae with GW7647, a potent PPARα agonist, enhanced the expression of hepatocyte markers and simultaneously reduced the expression of biliary epithelial cell (BEC)/LPC markers in the regenerating livers, indicating enhanced LPC-to-hepatocyte differentiation. Mechanistically, PPARα activation augments the differentiation by suppressing YAP signaling. The differentiation phenotypes resulting from GW7647 treatment were rescued by expressing a constitutively active form of Yap1. Moreover, we found that suppression of YAP signaling was sufficient to promote LPC-to-hepatocyte differentiation. Treating Tg(fabp10a:pt-β-catenin) larvae with the TEAD inhibitor K-975, which suppresses YAP signaling, phenocopied the effect of GW7647 on LPC differentiation. Altogether, our findings provide insights into augmenting LPC-mediated liver regeneration as a regenerative therapy for chronic liver diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping