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.