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Regulation of hepatic lipid metabolism by a novel Foxo pathway

新型 Foxo 途径调控肝脏脂质代谢

基本信息

批准号：
9018006
负责人：
X Charlie Dong
金额：
$ 33.93万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-25 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9018006
关键词：
Alleles Amines Anabolism Animal Model Biochemical Biology Blood Circulation Cardiovascular Diseases Circadian Rhythms Conflict (Psychology)DNA Data Development Diabetes Mellitus Diet Disease Dyslipidemias Enzymes Family member Fatty Liver Foxes Gene Expression Gene Expression Regulation Genes Genetic Goals Hepatic Hepatocyte Homeostasis Human Hypertriglyceridemia Insulin Insulin Resistance Insulin Signaling Pathway Knock-out Knowledge Laboratories Life Lipids Literature Liver Liver Circulation Liver diseases Mediating Messenger RNA Metabolic Diseases Mission Molecular Mus Obesity Pathway interactions Patients Physiological Physiological Processes Play Prevention Process Production Proteins Public Health Regulation Regulatory Pathway Reporting Research Role Signal Transduction Sirtuins Testing Triglycerides Very low density lipoprotein Wild Type Mouse Work base burden of illness design drug discovery fatty acid oxidation forkhead protein innovation insulin signaling knock-down lipid biosynthesis lipid metabolism member mouse model new therapeutic target nicotinamide phosphoribosyltransferase non-alcoholic fatty liver novel overexpression protein protein interaction transcriptomics western diet

项目摘要

DESCRIPTION (provided by applicant): Proper regulation of hepatic lipid metabolism is critical to triglyceride homeostasis in the liver and blood circulation. However, the underlying mechanism of the regulation remains elusive. The long-term goal of this laboratory is to better understand the regulatory mechanism of hepatic lipid metabolism. The objective in this particular application is to illustrate the role of Forkhead transcription factor O subfamily members (Foxos) and their potential downstream effector(s) in the development of hepatic steatosis and hypertriglyceridemia. Foxos have been implicated in the regulation of hepatic lipogenesis and very-low-density lipoprotein (VLDL) secretion. However, the role of Foxos in these processes is still controversial. To clarify the physiological functions of Foxos in hepatic lipid metabolism, mouse models have been estabolished. The preliminary data suggest that a novel regulation is involved in hepatic lipid metabolism through Foxo-controlled expression of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the NAD biosynthesis. To test this hypothesis, two specific aims are designed: 1) To elucidate the molecular mechanisms of Nampt gene regulation by Foxos; 2) To determine the physiological role of the Foxo pathway in hepatic lipid metabolism. Under the first aim, mechanistic studies will be performed to illustrate the details of protein-DNA and protein-protein interactions in the regulation of the Nampt gene. Under the second aim, gene overexpression and knockout approaches will be used to delineate the physiological and pathological roles of the newly identified pathway in hepatic lipid homeostasis. This application is innovative, because new animal models will be utilized and a distinct pathway will be examined. The proposed research is also significant, because it is expected to advance and expand understanding of how hepatic lipid metabolism is regulated. Ultimately, such knowledge has a potential to advance the prevention and/or treatment of dyslipidemia and fatty liver disease.

描述(由申请人提供)：适当调节肝脏脂肪代谢对肝脏和血液循环中甘油三酯的平衡至关重要。然而，监管的基本机制仍然难以捉摸。该实验室的长期目标是更好地了解肝脂代谢的调节机制。在这一特殊应用中的目的是阐明Forkhead转录因子O亚家族成员(FOXOS)及其潜在的下游效应因子(S)在肝脏脂肪变性和高甘油三酯血症发生中的作用。FOXOS与肝脏脂肪生成和极低密度脂蛋白(VLDL)分泌的调节有关。然而，FOXOS在这些过程中扮演的角色仍然存在争议。为了阐明FOXOS在肝脂代谢中的生理功能，建立了小鼠模型。初步数据表明，通过FOXO控制NAD生物合成的限速酶烟酰胺磷酸核糖基转移酶(NAMPT)的表达，一种新的调节参与了肝脏的脂质代谢。为了验证这一假说，我们设计了两个特定的目标：1)阐明FOXOS对NAMPT基因调控的分子机制；2)确定FOXO通路在肝脏脂质代谢中的生理作用。在第一个目标下，将进行机制研究，以阐明蛋白质-DNA和蛋白质-蛋白质相互作用在NAMPT基因调控中的细节。在第二个目标下，基因过表达和基因敲除方法将被用来描述新发现的途径在肝脏脂质稳态中的生理和病理作用。这一应用是创新的，因为将利用新的动物模型，并将检查一条独特的途径。这项拟议的研究也具有重要意义，因为它有望促进和扩大对肝脂代谢如何调节的理解。归根结底，这些知识有可能促进血脂异常和脂肪肝的预防和/或治疗。