Abstract
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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is characterized by an excessive accumulation of fat in the liver
In a gene set enrichment analysis (GSEA) of DKO livers relative to Pten–/– livers, we found enrichment of gene signatures related to lipogenesis and insulin signaling, including insulin receptor substrates (IRSs) targets and gene sets related to steroid biosynthesis, lipid biosynthesis, and fatty acid metabolism (Figure 2B and Table 1)
We have shown that this hyperactivation of AKT in the liver arises from a positive feedback loop that links YAP/TAZ and insulin receptor substrate 2 (IRS2)/ AKT signaling (Figure 10)
Summary
The most severe form of NAFLD, NASH, often progresses to liver cancer [1,2,3]. There are no effective therapies to prevent the incidence and progression of NAFLD or NASH [4]. This makes clarification of the detailed mechanisms of disease progression using appropriate animal models that much more urgent. Insulin signaling begins with the binding of insulin to the insulin receptor (IR) This phosphorylates insulin receptor substrates (IRSs) and subsequently triggers the recruitment of PI3K and the activation of AKT [5,6,7,8,9]. Excessive AKT activation leads to the development of NAFLD by promoting the maturation of the transcription factor SREBP1c [11, 12].
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