Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Cell Mol Gastroenterol Hepatol. 2022;13(6):1625-1647. doi: 10.1016/j.jcmgh.2022.02.015. Epub 2022 Feb 28.
BACKGROUND & AIMS: Dysregulation of liver lipid metabolism is associated with the development and progression of nonalcoholic fatty liver disease, a spectrum of liver diseases including nonalcoholic steatohepatitis (NASH). In the liver, insulin controls lipid homeostasis by increasing triglyceride (TAG) synthesis, suppressing fatty acid oxidation, and enhancing TAG export via very low-density lipoproteins. Downstream of insulin signaling, the mechanistic target of rapamycin complex 1 (mTORC1), is a key regulator of lipid metabolism. Here, we define the role of hepatic mTORC1 activity in mouse models of NASH and investigate the mTORC1-dependent mechanisms responsible for protection against liver damage in NASH.
Utilizing 2 rodent NASH-promoting diets, we demonstrate that hepatic mTORC1 activity was reduced in mice with NASH, whereas under conditions of insulin resistance and benign fatty liver, mTORC1 activity was elevated. To test the beneficial effects of hepatic mTORC1 activation in mouse models of NASH, we employed an acute, liver-specific knockout model of TSC1 (L-TSC-KO), a negative regulator of mTORC1.
L-TSC-KO mice are protected from and have improved markers of NASH including reduced steatosis, decreased circulating transaminases, and reduced expression of inflammation and fibrosis genes. Mechanistically, protection from hepatic inflammation and fibrosis by constitutive mTORC1 activity occurred via promotion of the phosphatidylcholine synthesizing enzyme, CCTα, and enhanced very low-density lipoprotein-triglyceride export. Additionally, activation of mTORC1 protected from hepatic steatosis via negative feedback of the mTORC2-AKT-FOXO-SREBP1c lipogenesis axis.
Collectively, this study identifies a protective role for liver mTORC1 signaling in the initiation and progression of NASH in mice via dual control of lipid export and synthesis.
肝脏脂质代谢失调与非酒精性脂肪性肝病（一种包括非酒精性脂肪性肝炎[NASH]的肝脏疾病谱）的发生和进展有关。在肝脏中，胰岛素通过增加甘油三酯(TAG)合成、抑制脂肪酸氧化和通过极低密度脂蛋白增强 TAG 输出来控制脂质稳态。在胰岛素信号转导的下游，雷帕霉素复合物 1(mTORC1)的机械靶标是脂质代谢的关键调节剂。在这里，我们定义了肝 mTORC1 活性在 NASH 小鼠模型中的作用，并研究了负责保护 NASH 中肝损伤的 mTORC1 依赖性机制。
利用 2 种促进啮齿动物 NASH 的饮食，我们证明在 NASH 小鼠中肝 mTORC1 活性降低，而在胰岛素抵抗和良性脂肪肝的情况下，mTORC1 活性升高。为了测试肝 mTORC1 激活在 NASH 小鼠模型中的有益作用，我们采用了 TSC1（L-TSC-KO）的急性、肝特异性敲除模型，这是 mTORC1 的负调节剂。
L-TSC-KO 小鼠可预防并改善 NASH 的标志物，包括减少脂肪变性、降低循环转氨酶和减少炎症和纤维化基因的表达。从机制上讲，通过促进磷酸胆碱合成酶 CCTα 和增强极低密度脂蛋白-TAG 输出，组成型 mTORC1 活性对肝炎症和纤维化的保护作用发生。此外，mTORC1 的激活通过 mTORC2-AKT-FOXO-SREBP1c 脂肪生成轴的负反馈作用来预防肝脂肪变性。
总的来说，这项研究确定了肝 mTORC1 信号在通过对脂质输出和合成的双重控制来预防和促进 NASH 小鼠中发生和进展的保护作用。
