Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer

J Clin Invest. 2018 Mar 1;128(3):1010-1025. doi: 10.1172/JCI95802. Epub 2018 Feb 5.


Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer; therefore, its prevention is an important clinical goal. Ablation of phosphatase and tensin homolog (PTEN) or the protein kinase Hippo signaling pathway induces liver cancer via activation of AKT or the transcriptional regulators YAP/TAZ, respectively; however, the potential for crosstalk between the PTEN/AKT and Hippo/YAP/TAZ pathways in liver tumorigenesis has thus far remained unclear. Here, we have shown that deletion of both PTEN and SAV1 in the liver accelerates the development of NAFLD and liver cancer in mice. At the molecular level, activation of YAP/TAZ in the liver of Pten-/- Sav1-/- mice amplified AKT signaling through the upregulation of insulin receptor substrate 2 (IRS2) expression. Both ablation of YAP/TAZ and activation of the Hippo pathway could rescue these phenotypes. A high level of YAP/ TAZ expression was associated with a high level of IRS2 expression in human hepatocellular carcinoma (HCC). Moreover, treatment with the AKT inhibitor MK-2206 or knockout of IRS2 by AAV-Cas9 successfully repressed liver tumorigenesis in Pten-/- Sav1-/- mice. Thus, our findings suggest that Hippo signaling interacts with AKT signaling by regulating IRS2 expression to prevent NAFLD and liver cancer progression and provide evidence that impaired crosstalk between these 2 pathways accelerates NAFLD and liver cancer.

Keywords: Hepatology; Metabolism; Mouse models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / metabolism
  • Cell Cycle Proteins / metabolism
  • Disease Progression
  • Fatty Liver / metabolism*
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Insulin Receptor Substrate Proteins / metabolism*
  • Liver Neoplasms / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • PTEN Phosphohydrolase / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • Transcription, Genetic


  • Cell Cycle Proteins
  • IRS2 protein, human
  • Insulin Receptor Substrate Proteins
  • Sav1 protein, mouse
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse