Regulation of hepatic lipid metabolism by a novel Foxo pathway

描述（由申请人提供）：肝脏脂质代谢的适当调节对于肝脏和血液循环中的甘油三酯稳态至关重要。然而，监管的根本机制仍然难以捉摸。本实验室的长远目标是更好地了解肝脏脂质代谢的调控机制。该特定应用的目的是阐明叉头转录因子 O 亚家族成员 (Foxos) 及其潜在下游效应子在肝脂肪变性和高甘油三酯血症的发展中的作用。 Foxos 参与肝脏脂肪生成和极低密度脂蛋白 (VLDL) 分泌的调节。然而，Foxos 在这些过程中的作用仍然存在争议。为了阐明Foxos在肝脏脂质代谢中的生理功能，建立了小鼠模型。初步数据表明，通过 Foxo 控制的烟酰胺磷酸核糖转移酶 (Nampt)（NAD 生物合成中的限速酶）的表达，肝脏脂质代谢涉及一种新的调节。为了检验这一假设，设计了两个具体目标：1）阐明Foxos对Nampt基因调控的分子机制； 2)确定Foxo途径在肝脏脂质代谢中的生理作用。第一个目标是进行机制研究，以阐明 Nampt 基因调节中蛋白质-DNA 和蛋白质-蛋白质相互作用的细节。在第二个目标下，基因过表达和敲除方法将用于描述新发现的途径在肝脂质稳态中的生理和病理作用。该应用具有创新性，因为将利用新的动物模型并检查独特的途径。拟议的研究也很重要，因为它有望推进和扩大对肝脏脂质代谢如何调节的理解。最终，这些知识有可能促进血脂异常和脂肪肝疾病的预防和/或治疗。 公共健康相关性：拟议的研究与公共健康相关，因为更好地了解肝脂质稳态的调节机制最终有望为预防和治疗血脂异常以及脂肪肝病和心血管疾病等相关疾病提供潜在的新药物靶点。因此，拟议的研究与 NIH 使命的一部分相关，即追求有助于延长健康寿命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.