Paradoxical Role of Yes‐Associated Protein (YAP) in Liver Injury and Regeneration following Acetaminophen Overdose

Acetaminophen (APAP) overdose is the major cause of Acute Liver Failure (ALF) in the Western world. Treatment options for APAP‐induced ALF are limited. Studies have shown that stimulating liver regeneration could be a potential treatment for ALF after APAP overdose. However, the mechanisms of liver regeneration after APAP overdose are not completely understood, which is the focus of research in our laboratory. We investigated the role of Yes associated protein (YAP), the downstream co‐activator of Hippo Signaling Pathway, in liver injury and regeneration following APAP overdose. Previous studies have shown that YAP is involved in stimulation of hepatocyte proliferation. Treatment of two‐three months old C57BL/6 male mice with 300 mg/kg APAP (APAP 300) resulted in significant liver injury and regeneration over a time course of 0 to 96 hr. Increased activation of YAP was observed during initial time points (3, 6 and 12 hr) after APAP administration which coincided with both injury and regeneration. To determine whether YAP activation plays a role in injury or regeneration, we generated hepatocyte specific YAP knockout mice (hYAP‐KO) using YAP‐floxed mice treated with AAV8.TGB.Cre. Hepatocyte specific deletion of YAP did not change hepatic CYP2E1, the enzyme involved in APAP bioactivation, and hepatic glutathione (GSH) levels. Consistent with these data, no difference in APAP‐protein adducts was observed between control and hYAP‐KO mice after APAP treatment. Liver injury measured by serum ALT and histopathology showed extensive and similar liver injury up to 12 hr after APAP treatment in both control and hYAP‐KO mice. However, the progression of the liver injury beyond 12 hr after APAP administration was significantly lower in hYAP‐KO mice as compared with control mice. The decrease in progression of liver injury was accompanied with an earlier decrease in JNK activation and faster GSH recovery in hYAP‐KO mice. Additionally, the hYAP‐KO mice showed an early induction of proliferative markers demonstrating early liver regeneration as compared to the control mice. These data indicate that hepatocyte specific activation of YAP may be involved in progression of liver injury and may inhibit liver regeneration after APAP overdose. These findings indicate a novel paradoxical role of YAP in APAP overdose and highlight YAP as a potential therapeutic target for the treatment of APAP‐induced ALF. Support or Funding Information NIH (5P20RR021940‐07, T32ES007079‐32, R01DK098414) And the Liver Scholar Award by AASLD/American Liver Foundation