Hepatic mTORC1 Signaling and the Regulation of Lipid Homeostasis

与脂质代谢改变相关的疾病，如非酒精性脂肪性肝病（NAFLD）和动脉粥样硬化是美国人口的重大健康威胁。因此，必须明确驱动异常脂质稳态的分子机制，以确定新的有效治疗方法。胰岛素抵抗是血脂功能障碍的重要危险因素之一；然而，我们对异常胰岛素作用如何导致代谢疾病中脂质代谢改变的理解仍然存在重大知识空白。肝脏负责调节脂质产生和分解的速率，以控制全身脂质稳态。这些过程的失调是血脂异常和NAFLD发病机制的基础，后者由一系列肝脏疾病组成，包括单纯性肝脂肪变性（NAFL）和非酒精性脂肪性肝炎（NASH）。包括我们在内的几个实验室的研究表明，肝脏胰岛素信号通过AKT-mTORC1途径参与脂质代谢的调节。我们实验室最近的工作揭示了肝脏mTORC1信号在磷脂代谢调节中的新功能，这对于胰岛素适当控制肝脏和全身脂质水平至关重要。这一发现对NAFLD和血脂异常具有重要意义，并为胰岛素信号通过mTORC1调节脂质代谢的作用提供了重要的机制见解。在本提案的目标1中，我们将以这些重要的观察结果为基础，定义mTORC1控制磷脂酰胆碱生物合成和肝脂质稳态的分子机制。在Aim 2中，我们将利用多种NASH模型探索操纵肝脏mTORC1信号在NAFLD发生和发展中的治疗潜力。总的来说，这一建议将建立在最近关于胰岛素信号通过mTORC1在肝脏脂质代谢调节中的作用的发现之上。这些实验有可能显著影响我们对连接异常胰岛素信号与NAFLD和血脂异常的代谢途径的机制理解，这将为脂肪肝疾病和前动脉粥样硬化性血脂异常的新治疗靶点提供基础。

Disorders associated with altered lipid metabolism such as non-alcoholic fatty liver disease (NAFLD) and atherosclerosis are a significant health threat to the U.S. population. As result, it is imperative to define the molecular mechanisms driving abnormal lipid homeostasis to identify new and effective therapeutics. Insulin- resistance is one of the most significant risk factors for lipid dysfunction; however, significant knowledge gaps remain in our understanding of how abnormal insulin action leads to altered lipid metabolism in metabolic disease. The liver is responsible for regulating the rates of lipid production and breakdown to control systemic lipid homeostasis. Dysregulation of these processes underly the pathogenesis of dyslipidemia and NAFLD, the latter consisting of a spectrum of liver diseases that encompasses simple liver steatosis (NAFL) and non- alcoholic steatohepatitis (NASH). Work by several laboratories including ours have implicated liver insulin signaling via the AKT-mTORC1 pathway in the regulation of lipid metabolism. Recent work from our laboratory uncovered a novel function for liver mTORC1 signaling in the regulation of phospholipid metabolism that is essential for the proper control of both hepatic and systemic lipid levels by insulin. This discovery has important implications to NAFLD and dyslipidemia and adds significant mechanistic insight into the role of insulin signaling via mTORC1 in the regulation of lipid metabolism. In Aim 1 of this proposal, we will build on these important observations and define the molecular mechanism underlying mTORC1's control of phosphatidylcholine biosynthesis and hepatic lipid homeostasis. In Aim 2, we will explore the therapeutic potential of manipulating liver mTORC1 signaling in the initiation and progression of NAFLD using multiple models of NASH. Collectively, this proposal will build upon recent discoveries regarding the role of insulin signaling via mTORC1 in the regulation of hepatic lipid metabolism. These experiments have the potential to significantly affect our mechanistic understand of the metabolic pathways that connect abnormal insulin signaling to NAFLD and dyslipidemia, which will provide the foundation for new therapeutic targets for fatty liver disease and pro- atherogenic dyslipidemia.