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

Abstract

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 during postnatal liver growth, regeneration after partial hepatectomy and during liver cancer pathogenesis. Treatment of two-three month old C57BL/6J 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) by treating two-three month old male YAP-floxed mice with AAV8.TGB.Cre. Hepatocyte specific deletion of YAP neither caused liver injury, nor did it change hepatic CYP2E1 expression 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 to control mice. The decrease in progression of liver injury was accompanied with an earlier decrease in JNK activation and faster GSH recovery. 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. Linked to that, hepatocytes specific deletion of YAP results in earlier onset of regeneration after APAP overdose. These findings indicate a differential role of YAP in APAP overdose and highlight YAP as a potential therapeutic target for the treatment of APAP-induced ALF.