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Hepatic mTORC1 Signaling and the Regulation of Lipid Homeostasis

肝脏 mTORC1 信号转导和脂质稳态的调节

基本信息

批准号：
10352468
负责人：
Paul Michael Titchenell
金额：
$ 42.84万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10352468
关键词：
Acceleration Acute Affect Anabolism Arterial Fatty Streak Atherogenic Diet Atherosclerosis Automobile Driving Biogenesis Biological Cardiometabolic Disease Cell Death Cell Proliferation Cell physiology Cholesterol Communities Cytidine Diphosphate Choline Development Diet Disease Dyslipidemias Enzymes Fatty Liver Fatty acid glycerol esters Foundations Fructose Functional disorder Genetic Genetic Epistasis Goals Health Hepatic Hepatocyte Homeostasis Human In Vitro Insulin Insulin Resistance Intervention Studies Kinetics Knockout Mice Knowledge Laboratories Lecithin Leucine Lipids Lipoproteins Liver Liver Dysfunction Liver Fibrosis Liver diseases Low-Density Lipoproteins Mammalian Cell Measures Mediating Metabolic Diseases Metabolic Pathway Metabolism Modeling Modification Molecular Mus Mutagenesis Nutrient Nutritional Pathogenesis Pathway interactions Phenotype Phosphatidylcholine Biosynthesis Phospholipid Metabolism Phospholipids Phosphorylation Phosphorylation Site Population Process Production Proteins Proto-Oncogene Proteins c-akt Regulation Research Risk Risk Factors Role Signal Transduction Structure TSC1 gene Testing Therapeutic Therapeutic Effect Translating Triglycerides Tumor Suppressor Proteins Very low density lipoprotein Work cell growth choline deficient diet detection of nutrient effectiveness testing experimental study fatty liver disease feeding in vivo insight insulin signaling lipid disorder lipid metabolism liver function loss of function mutation mouse model new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel prevent therapeutically effective uptake

项目摘要

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.

与脂质代谢改变相关的疾病，如非酒精性脂肪肝（NAFLD）和动脉粥样硬化，是对美国人口的重大健康威胁。因此，必须确定驱动异常脂质稳态的分子机制，以确定新的和有效的治疗方法。胰岛素抵抗是脂质功能障碍的最重要的危险因素之一;然而，在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中，仍然存在重大的知识缺口。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的发病机制的基础，后者由包括单纯性肝脂肪变性（NAFL）和非酒精性脂肪性肝炎（NASH）的一系列肝脏疾病组成。包括我们在内的几个实验室的工作表明，肝脏胰岛素信号通过AKT-mTORC 1途径调节脂质代谢。我们实验室最近的工作揭示了肝脏mTORC 1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，并为通过mTORC 1调节脂质代谢中胰岛素信号传导的作用提供了重要的机制见解。在本提案的目标1中，我们将建立在这些重要的观察结果的基础上，并定义mTORC 1控制磷脂酰胆碱生物合成和肝脏脂质稳态的分子机制。在目标2中，我们将使用多种NASH模型探索操纵肝脏mTORC 1信号传导在NAFLD的起始和进展中的治疗潜力。总的来说，这项建议将建立在最近发现的胰岛素信号通过mTORC 1在调节肝脏脂质代谢的作用。这些实验有可能显著影响我们对将异常胰岛素信号传导与NAFLD和血脂异常联系起来的代谢途径的机制理解，这将为脂肪肝疾病和促动脉粥样硬化性血脂异常的新治疗靶点提供基础。