The Hippo pathway effector YAP controls mouse hepatic stellate cell activation

Area of Science:

• Hepatology
• Cell Biology
• Molecular Biology

Background:

• Hepatic stellate cell activation is crucial for liver wound healing.
• Sustained activation leads to liver fibrosis and cirrhosis.
• Early activation mechanisms remain poorly understood.

Purpose of the Study:

• To investigate the role of the Hippo pathway and its effector YAP in hepatic stellate cell activation.
• To elucidate the mechanisms driving early stellate cell activation.
• To explore YAP inhibition as a therapeutic strategy for liver fibrosis.

Main Methods:

• In vivo studies using CCl4-induced liver injury in mice.
• In vitro activation of hepatic stellate cells.
• YAP (Yes-associated protein) activation assessment via nuclear translocation and target gene induction.
• YAP knockdown and pharmacological inhibition.

Main Results:

• The Hippo pathway and YAP were identified as key regulators of hepatic stellate cell activation.
• YAP activation, indicated by nuclear translocation, drives early gene expression changes.
• YAP was activated in hepatic stellate cells in both mouse models and human fibrotic livers.
• YAP inhibition prevented hepatic stellate cell activation and impeded liver fibrogenesis in mice.

Conclusions:

• YAP activation is a critical driver of hepatic stellate cell activation.
• Inhibition of YAP represents a novel therapeutic approach for treating liver fibrosis.