PROJECT 4 (NI): PROJECT SUMMARY Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent form of liver disease associated with obesity, diabetes and other metabolic diseases. The molecular basis of the development of NAFLD and obesity are still poorly understood. As a result, no effective therapeutic treatments for this burgeoning health problem are available. Thus, there is a clear unmet research need in this area. Liver can modulate the processes of NAFLD and other metabolic comorbidities including obesity by secreting hepatokines. Adropin is one of the hepatokines involved in glucose and lipid metabolism, energy homeostasis, insulin sensitivity and NAFLD. Hepatic very-low- density lipoprotein (VLDL) secretion is essential in regulating intrahepatic and intravascular lipid homeostasis, and impaired VLDL secretion leads to steatosis. Vacuole membrane protein 1 (VMP1) is an ER membrane protein that regulates autophagy by promoting the closure of autophagosomes. Recent evidence demonstrates that VMP1 plays a critical role in lipoprotein secretion independent of its autophagy function in cultured hepatoma cells and zebrafish. However, the mechanisms by which VMP1 regulates lipid metabolism, adropin or other hepatokine secretion and obesity are unclear. The major OBJECTIVES of this application are to investigate novel mechanisms by which VMP1 regulates VLDL and adropin secretion as well as the liver-adipose crosstalk in the pathogenesis of NAFLD and its impact on obesity. Our proposal is SIGNIFICANT because it is to investigate a novel pathway in regulating lipid metabolism and adropin secretion which regulate the development of NAFLD and obesity. Work performed under this application will enrich the field regarding the critical role of VMP1 as a central regulator which regulate VLDL and adropin secretion in the development of NAFLD and obesity. Our overall SCIENTIFIC PREMISE is that elucidating pathways whereby VMP1 improves VLDL and adropin secretion and protects NAFLD and obesity. Our proposal is supported by KEY PRELIMINARY DATA including: 1) Hepatocyte-specific deletion of VMP1 in mice impaired VLDL secretion resulting in hepatic steatosis; 2) Loss of hepatic VMP1 severely impaired VLDL secretion associated with markedly decreased COPII complex proteins; 3) Overexpression of VMP1 in mouse livers protected high fat diet (HFD)–induced liver steatosis, hyperlipidemia and obesity, which was associated with increased serum adropin levels. Two SPECIFIC AIMS are proposed: 1) Determine the mechanisms by which loss of VMP1 decreases COPII and ERGIC-53 that impairs adropin ER-Golgi trafficking and secretion; 2) Determine the role of VMP1 in mediating adropin secretion and regulating liver-adipose crosstalk in NAFLD and obesity. The LONGTERM GOAL of this work is to identify VMP1-dependent pathways in the pathogenesis of NAFLD and obesity and develop potential strategies for prevention and treatment of NAFLD and obesity by improving VMP1-mediated VLD...