Selective mTORC1 inhibition to prevent and treat NAFLD and NASH

在美国，有多达1亿人患有非酒精性脂肪性肝病(NAFLD)，这可能导致肝脏损伤和纤维化，表现为非酒精性脂肪性肝炎(NASH)，进而可能发展为肝硬变和肝细胞癌(HCC)。到目前为止，还没有FDA批准的治疗NAFLD或NASH的方法。在包括肝细胞在内的多种细胞中，mTOR通路是一条重要的营养感应通路。因此，mTORC1已被研究为调节肝脏中脂质动态平衡的靶点，但其作用尚不清楚，多项出色的研究导致了似乎相反的结论。我们现在已经在肝脏中发现了mTORC1信号的一个高度特异的分支，受Flcn蛋白的调控，该信号的抑制导致脂质分解代谢途径的协调激活和对新生脂肪生成(DNL)的强烈抑制，从而有效地保护NAFLD和随后的NASH。因此，我们假设FLCN是治疗这些疾病的一个独特的有吸引力的治疗靶点。我们提出实验的目的是：1.从机制上了解mTORC1信号的FLCN臂如何抑制DNL 2.从机制上了解mTORC1信号的FLCN和规范臂如何相互反馈3.正式测试FLCN作为治疗NAFLD/NASH/HCC谱的治疗靶点的有效性。

As many as 100 million people in the US have non-alcoholic fatty liver disease (NAFLD), which can lead to hepatic injury and fibrosis, characteristics of non-alcoholic steatohepatitis (NASH), and in turn can progress to cirrhosis and hepatocellular carcinoma cancer (HCC). To date there are no FDA-approved therapy for NAFLD or NASH. The mTOR pathway is a critical nutrient sensing pathway in many cell types, including hepatocytes. mTORC1 has thus been studied as a target to modulate lipid homeostasis in the liver, but its role remains unclear, with multiple excellent studies lead to seemingly opposing conclusions. We have now uncovered a highly specific branch of mTORC1 signaling in the liver, regulated by the FLCN protein, the inhibition of which leads to coordinated activation of lipid catabolic pathways and strong suppression of de novo lipogenesis (DNL), thereby potently protecting from both NAFLD and ensuing NASH. We thus hypothesize that FLCN represents a uniquely attractive therapeutic target to treat these diseases. We propose experiments to: 1. Understand how, mechanistically, the FLCN arm of mTORC1 signaling suppresses DNL 2. Understand how, mechanistically, the FLCN and canonical arms of mTORC1 signaling feedback on each other 3. Formally test the validity of FLCN as a therapeutic target to treat the NAFLD/NASH/HCC spectrum.