PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish

by Selleckchem | Jan 22 2024

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.

Comments:

That's an intricate study demonstrating the potential of PPARα activation in promoting LPC-to-hepatocyte differentiation, crucial for liver regeneration. It seems the activation of PPARα affects the expression of hepatocyte and biliary epithelial cell markers, indicating a shift toward hepatocyte differentiation.

The involvement of YAP signaling in this process is fascinating. The suppression of YAP signaling through PPARα activation suggests a mechanism through which hepatocyte differentiation is enhanced. Additionally, the rescue experiment using a constitutively active form of Yap1 further supports the role of YAP signaling in this differentiation process.

The use of the zebrafish model allows for intricate investigations into the molecular mechanisms underlying liver regeneration. The findings have implications for potential regenerative therapies for chronic liver diseases, suggesting that modulating PPARα or targeting the YAP signaling pathway could be a promising approach.

Translating these findings into clinical applications could be groundbreaking for developing therapies aimed at enhancing liver regeneration in patients with chronic liver diseases. However, further research would likely be needed to validate these findings in mammalian models and eventually in clinical trials.