Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
International Cooperation Laboratory on Signal Transduction, Second Military Medical University, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
Cell Death Dis. 2019 Aug 14;10(8):619. doi: 10.1038/s41419-019-1828-2.
Hepatocellular carcinoma (HCC) can be the last step of nonalcoholic fatty liver disease (NAFLD) evolution, and the main characteristic of NAFLD is alteration in lipid metabolism. However, the mechanisms of abnormal lipid metabolism in NAFLD and HCC progression are yet to be identified. Here, we demonstrate that liver-specific activation of mTORC1 promoted the expression of lipid synthesis genes and lead to the development of spontaneous HCC. Genetic mouse models developed spontaneous HCC along with increased expressions of SREBP1, ACC1 and FASN. In addition, high levels of p-STAT5 were observed in the livers and particularly evident in the tumor area. And the synthesis of p-STAT5 was increased in patients along with the increase in SREBP1 synthesis in clinical samples. Moreover, mTORC1 interacts with and phosphorylates the STAT5 in hepatocytes. In conclusion, our data suggested that mTORC1 upregulates SREBP1 transcription via crosstalk with the STAT5 pathway which contributes to the NAFLD-related HCC pathogenesis. And the inhibitor of SREBP1 and mTOR may help to prevent HCC in clinical NAFLD patients.
肝细胞癌 (HCC) 可能是非酒精性脂肪性肝病 (NAFLD) 演变的最后一步，NAFLD 的主要特征是脂质代谢改变。然而，NAFLD 和 HCC 进展中异常脂质代谢的机制仍有待确定。在这里，我们证明了 mTORC1 在肝脏中的特异性激活促进了脂质合成基因的表达，并导致自发性 HCC 的发生。遗传小鼠模型自发发生 HCC，同时 SREBP1、ACC1 和 FASN 的表达增加。此外，在肝脏中观察到高水平的 p-STAT5，在肿瘤区域尤为明显。并且在临床样本中，随着 SREBP1 合成的增加，p-STAT5 的合成也增加。此外，mTORC1 在肝细胞中相互作用并磷酸化 STAT5。总之，我们的数据表明，mTORC1 通过与 STAT5 通路的串扰上调 SREBP1 转录，这有助于 NAFLD 相关 HCC 的发病机制。SREBP1 和 mTOR 的抑制剂可能有助于预防临床 NAFLD 患者的 HCC。
