Selective mTORC1 inhibition to prevent and treat NAFLD and NASH

美国有多达1亿人患有非酒精性脂肪性肝病（NAFLD），这可能导致肝损伤和纤维化，这是非酒精性脂肪性肝炎（NASH）的特征，进而可能进展为肝硬化和肝细胞癌（HCC）。迄今为止，没有FDA批准的NAFLD或NASH治疗。mTOR途径是许多细胞类型（包括肝细胞）中的关键营养感应途径。因此，mTORC 1已被研究为调节肝脏脂质稳态的靶点，但其作用仍不清楚，多项出色的研究得出了看似相反的结论。我们现在已经发现了肝脏中mTORC 1信号传导的高度特异性分支，由FLCN蛋白调节，其抑制导致脂质分解代谢途径的协调激活和新生脂肪生成（DNL）的强烈抑制，从而有效地保护免于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。我们提出的实验：1。了解mTORC 1信号的FLCN臂如何在机制上抑制DNL 2。了解FLCN和mTORC 1信号传导的规范臂如何在机制上相互反馈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.