PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish
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-medi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-44935-5 |
| _version_ | 1797453127033552896 |
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| author | Minwook Kim Juhoon So Donghun Shin |
| author_facet | Minwook Kim Juhoon So Donghun Shin |
| author_sort | Minwook Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T15:18:25Z |
| format | Article |
| id | doaj.art-47d30b5522df4a069689e106e6fcb58a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:18:25Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-47d30b5522df4a069689e106e6fcb58a2023-11-26T12:55:26ZengNature PortfolioScientific Reports2045-23222023-10-0113111110.1038/s41598-023-44935-5PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafishMinwook Kim0Juhoon So1Donghun Shin2Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of PittsburghDepartment of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of PittsburghDepartment of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of PittsburghAbstract 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.https://doi.org/10.1038/s41598-023-44935-5 |
| spellingShingle | Minwook Kim Juhoon So Donghun Shin PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish Scientific Reports |
| title | PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish |
| title_full | PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish |
| title_fullStr | PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish |
| title_full_unstemmed | PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish |
| title_short | PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish |
| title_sort | pparα activation promotes liver progenitor cell mediated liver regeneration by suppressing yap signaling in zebrafish |
| url | https://doi.org/10.1038/s41598-023-44935-5 |
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