Regulation of hepatic lipid metabolism by a novel Foxo pathway

描述（由申请人提供）：适当调节肝脏脂质代谢对肝脏和血液循环中的甘油三酯稳态至关重要。然而，监管的潜在机制仍然难以捉摸。本实验室的长期目标是更好地了解肝脏脂质代谢的调节机制。这项特殊应用的目的是阐明叉头转录因子O亚家族成员（Foxos）及其潜在的下游效应物在肝脂肪变性和高甘油三酯血症发展中的作用。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，我们建立了小鼠模型。初步数据表明，通过foxo控制NAD生物合成中的限速酶烟酰胺磷酸核糖基转移酶（Nampt）的表达，一种新的调节机制参与了肝脏脂质代谢。为了验证这一假设，我们设计了两个特定的目标：1)阐明Foxos调控Nampt基因的分子机制；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，以说明蛋白质- 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。这个应用是创新的，因为新的动物模型将被利用，一个独特的途径将被检查。提出的研究也很重要，因为它有望推进和扩大对肝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。

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.