Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany.
Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University Hospital, Aachen, Germany.
Neoplasia. 2023 Dec;46:100945. doi: 10.1016/j.neo.2023.100945. Epub 2023 Nov 15.
Obesity and associated nonalcoholic steatohepatitis (NASH) are on the rise globally. NASH became an important driver of hepatocellular carcinoma (HCC) in recent years. Activation of the central metabolic regulator mTOR (mechanistic target of rapamycin) is frequently observed in HCCs. However, mTOR inhibition failed to improve the outcome of HCC therapies, demonstrating the need for a better understanding of the molecular and functional consequences of mTOR blockade. We established a murine NASH-driven HCC model based on long-term western diet feeding combined with hepatocellular mTOR-inactivation. We evaluated tumor load and whole-body fat percentage via µCT-scans, analyzed metabolic blood parameters and tissue proteome profiles. Additionally, we used a bioinformatic model to access liver and HCC mitochondrial metabolic functions. The tumor burden was massively increased via mTOR-knockout. Several signs argue for extensive metabolic reprogramming of glucose, fatty acid, bile acid and cholesterol metabolism. Kinetic modeling revealed reduced oxygen consumption in KO-tumors. NASH-derived HCC pathogenesis is driven by metabolic disturbances and should be considered separately from those caused by other etiologies. We conclude that mTOR functions as tumor suppressor in hepatocytes especially under long-term western diet feeding. However, some of the detrimental consequences of this diet are attenuated by mTOR blockade.
肥胖症和相关的非酒精性脂肪性肝炎（NASH）在全球范围内呈上升趋势。近年来，NASH 已成为肝细胞癌（HCC）的重要驱动因素。中央代谢调节剂 mTOR（雷帕霉素的作用靶点）的激活在 HCC 中经常观察到。然而，mTOR 抑制未能改善 HCC 治疗的结果，这表明需要更好地了解 mTOR 阻断的分子和功能后果。我们建立了一种基于长期西方饮食喂养结合肝细胞 mTOR 失活的小鼠 NASH 驱动的 HCC 模型。我们通过 µCT 扫描评估肿瘤负荷和全身脂肪百分比，分析代谢血液参数和组织蛋白质组谱。此外，我们使用生物信息模型来评估肝脏和 HCC 线粒体代谢功能。通过 mTOR 敲除，肿瘤负担大大增加。有几个迹象表明葡萄糖、脂肪酸、胆汁酸和胆固醇代谢的广泛代谢重编程。动力学建模显示 KO 肿瘤的耗氧量降低。NASH 衍生的 HCC 发病机制是由代谢紊乱驱动的，应与其他病因引起的代谢紊乱分开考虑。我们得出的结论是，mTOR 在肝细胞中作为肿瘤抑制因子发挥作用，特别是在长期西方饮食喂养下。然而，这种饮食的一些有害后果被 mTOR 阻断所减轻。
