Hippo/YAP Signaling Induced by Endotoxin Promotes Kupffer Cell Activation and Hepatic Inflammation in Non-Alcoholic Fatty Liver Disease (NFALD)

Recent studies show that the Hippo pathway and its downstream effector YAP play important roles in organ size control, liver fibrosis and hepatocarcinogenesis. However, it remains unknown whether Hippo/YAP signaling is implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). This study was designed to investigate the potential role of Hippo/YAP signaling in a mouse model of high-fat diet (HFD)-induced NAFLD. Male C57BL/6 mice were fed a normal chow diet (NCD) or HFD (60% kcal fat) for 12 wks. Intraperitoneal injections of low-dose lipopolysaccharide (LPS: 0.25mg/kg) were administered daily for 3 wks to NCD-fed mice. Upregulation of YAP in Kupffer cells was observed in HFD-fed mice and LPS-treated mice. Our data indicated that LPS induced AP-1 binding to their consensus site in the YAP gene promoter which leads to enhanced YAP gene transcription. In contrast, the protein level of MST1, an upstream kinase that inactivates YAP, was decreased by LPS treatment. We observed that overexpressi...