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

Abstract

IntroductionNAFLD is characterized by an excessive accumulation of fat in the liver. The most severe form of NAFLD, NASH, often progresses to liver cancer (1-3). Tracking with the increasing prevalence of general obesity, 30% of the US population is now estimated to have NAFLD, and 25% of these individuals will develop NASH (1, 3). Currently, 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 then phosphorylates insulin receptor substrates (IRSs) and subsequently triggers the recruitment of PI3K and the activation of AKT (5-9). Deletion of IRS1 and IRS2 in the mouse liver reduces AKT activity and gives rise to insulin resistance (10). Excessive AKT activation leads to the development of NAFLD by promoting the maturation of the transcription factor SREBP1c (11,12). In its mature form, SREBP1c contributes to the induction of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), which are key enzymes in de novo lipogenesis (13). Phosphatase and tensin homolog (PTEN) is a negative regulator of AKT signaling, and several human cancers are associated with mutations or downregulation of the PTEN gene (14-16). Liver-specific PTEN-knockout mice progressively develop NAFLD, NASH, and HCC (17, 18) as a result of increased AKT signaling (19).The Hippo signaling pathway has been implicated in the suppression of tissue regeneration, the proliferation of stem cells, and the development of cancer by inhibiting the oncogenic activity of the transcriptional coactivators YAP and TAZ (20,21). In mice, liverspecific knockout of the Hippo pathway components MST1/2, SAV1, or NF2 induces the expansion of hepatic progenitor cells via YAP/TAZ activation and leads eventually to the development of liver cancer (HCC, cholangiocarcinoma [CC], or both) (22)(23)(24)(25). Despite its importance in tumorigenesis, the role of Hippo signaling in the metabolic dysregulation that precedes the development of liver cancer remains unclear.Previous studies have suggested that YAP regulates components of the AKT pathway (i.e., PI3K, PTEN, and AKT) and that the Drosophila Hippo ortholog MST1 binds and inhibits AKT directly (26)(27)(28)(29). Increased YAP expression in human liver tumors is associated with high levels of p- AKT (30,31). This suggests that crosstalk between the Hippo and AKT pathways may be important in the maintenance of functional liver homeostasis. The molecular coordination of these 2 pathways in liver tumorigenesis, however, has not been revealed. Using several mouse models, we now show 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 transc...

Hepatocyte Stress Increases Expression of Yes‐Associated Protein and Transcriptional Coactivator With PDZ‐Binding Motif in Hepatocytes to Promote Parenchymal Inflammation and Fibrosis

“…In response to organ injury, there is a complex dance that cells orchestrate to result in functional regeneration. YAP/TAZ have a long‐established role in regulating cell proliferation and survival and are increasingly being recognized to have other roles such as controlling cellular metabolism . These primarily are cell‐autonomous activities, but proper organ regeneration also requires coordinating critical non‐cell‐autonomous activities, including the removal of dead/dying cells, generation of extracellular matrices, and defining cell/organ polarity.…”

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…[ 97 ] Whole liver Albumin‐Cre Pten flox/flox Sav flox/flox double knockouts rapidly developed HCC tumors within 5 months and this phenotype was suppressed to normal size by crossing with Yap flox/flox and Taz flox/flox to produce a quadruple knockout. [ 98 ] Hydrodynamic transfection of both PI3K ( PIK3CA H1047R ) and Yap S127A also produced HCC. [ 99 ] Furthermore, expression of strongly active Yap 5SA by hydrodynamic transfection of livers was sufficient to induce large HCC‐like tumors within 5 months and to recruit type II macrophages to induce immune evasion, which was required for tumorigenesis.…”

Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease

“…Furthermore, YAP knockout completely abrogated the regenerative capacity of rodent hepatocytes, highlighting the crucial role of Hippo signaling in controlling liver regeneration (Pepe‐Mooney et al, ). Interestingly, previous studies had also shown that suppression of IRS2/AKT by Hippo signaling can protect against steatosis and liver cancer progression (Jeong et al, ) and found YAP increased in multiple NAFLD models, in which expression and accumulation of YAP correlated with hepatocyte injury severity (P. Chen et al, ; Jeong et al, ; Kodama et al, ; Machado et al, ).…”