(The) crosstalk between hippo and AKT signaling pathways in the development of non-alcoholic fatty liver disease and liver cancer

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer, with its prevention therefore being an important clinical goal. Ablation of PTEN or Hippo signaling pathway components induces liver cancer via activation of AKT and of YAP/TAZ, respectively. However, the possible role of cross talk between Hippo-YAP/TAZ and PTEN-AKT pathways in liver tumorigenesis has remained unclear. Here I show that deletion of both Pten and Sav1 in the liver accelerated the development of NAFLD and liver cancer in mice through excessive activation of AKT. Activation of YAP/TAZ in the $Pten^{-/-}

Sav1^{-/-}$ liver amplified AKT signaling through up-regulation of insulin receptor substrate 2 (IRS2) expression. A high level of YAP or TAZ expression was also associated with a high level of IRS2 expression in human liver disease. Moreover, treatment with the AKT inhibitor MK-2206 attenuated NAFLD development and liver tumorigenesis in $Pten^{-/-}

Sav1^{-/-}$ mice. My findings thus suggest that cross talk between Hippo and AKT signaling pathways at the level of YAP/TAZ and IRS2 contributes to the development and progression of NAFLD, and they therefore provide a basis for the development of new therapeutic interventions.