Regulation of hepatic lipid metabolism by a novel Foxo pathway

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。 公共卫生相关性：拟议的研究与公共健康相关，因为更好地了解肝脏脂质稳态背后的调节机制最终有望为预防和治疗血脂异常和相关疾病(如脂肪肝和心血管疾病)提供潜在的新药物靶点。因此，拟议的研究与NIH使命的一部分有关，该使命涉及寻求有助于延长健康生活和减轻疾病负担的基础知识。

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because better understanding of the regulatory mechanisms underlying hepatic lipid homeostasis is ultimately expected to provide potential novel drug targets for the prevention and treatment of dyslipidemia and related disorders such as fatty liver disease and cardiovascular disease. Thus, the proposed research is relevant to the part of NIH's mission that pertains to pursuing fundamental knowledge that will help to extend healthy life and reduce the burdens of illness.