National Creative Research Initiatives Center, Department of Biological Sciences, Biomedical Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
BMB Rep. 2018 May;51(5):209-210. doi: 10.5483/bmbrep.2018.51.5.095.
NAFLD induces the development of advanced liver diseases such as NASH and liver cancer. Therefore, understanding the mechanism of NAFLD development is critical for its prevention and treatment. Ablation of PTEN or Hippo pathway components induces liver cancer in a murine model by hyperactive AKT or YAP/TAZ, respectively. Although the regulation of these two pathways occurs in the same hepatocyte, the details of crosstalk between Hippo-YAP/TAZ and PTEN-AKT pathways in liver homeostasis and tumorigenesis still remain unclear. Here, we found that depletion of both PTEN and SAV1 in liver promotes spontaneous NAFLD and liver cancer through hyperactive AKT via YAP/TAZmediated up-regulation of IRS2 transcription. Conversely, NAFLD is rescued by both ablation of YAP/TAZ and activation of the Hippo pathway. Furthermore, human HCC patients with NAFLD showed strong correlation between YAP/TAZ and IRS2 or phospho-AKT expression. Finally, the inhibition of AKT by MK-2206 treatment attenuates NAFLD development and tumorigenesis. Our findings indicate that Hippo pathway interacts with AKT signaling during the intervention with IRS2 to prevent NAFLD and liver cancer. [BMB Reports 2018; 51(5): 209-210].
非酒精性脂肪性肝病（NAFLD）可诱导非酒精性脂肪性肝炎（NASH）和肝癌等晚期肝脏疾病的发生。因此，了解 NAFLD 发生发展的机制对于其预防和治疗至关重要。PTEN 或 Hippo 通路成分的缺失分别通过 AKT 或 YAP/TAZ 的过度激活在小鼠模型中诱导肝癌的发生。尽管这两条通路的调节发生在同一肝细胞中，但 Hippo-YAP/TAZ 和 PTEN-AKT 通路在肝脏稳态和肿瘤发生中的相互作用的细节仍不清楚。在这里，我们发现肝脏中同时敲除 PTEN 和 SAV1 通过 YAP/TAZ 介导的 IRS2 转录上调导致 AKT 过度激活，从而促进自发性 NAFLD 和肝癌的发生。相反，通过敲除 YAP/TAZ 和激活 Hippo 通路可挽救 NAFLD。此外，伴有 NAFLD 的人类 HCC 患者的 YAP/TAZ 和 IRS2 或磷酸化 AKT 表达之间存在强烈相关性。最后，MK-2206 抑制 AKT 的作用可减弱 NAFLD 的发生发展和肿瘤发生。我们的研究结果表明，在 IRS2 的干预下，Hippo 通路与 AKT 信号通路相互作用，以防止 NAFLD 和肝癌的发生。[BMB 报告 2018;51(5):209-210]。
