Obesity is associated with ectopic deposition of fats which lead to lipotoxicity and chronic inflammation in various tissues. The long term goal of this study is to understand the mechanisms by which saturated fatty acid (SFA) induce endothelial dysfunction and its consequences in metabolic and cardiovascular disorders. Macroautophagy (hereafter autophagy) is initiated by the nucleation of membrane-like structure and encloses cargo (proteins, lipid, and organelles) in membranous structure (autophagosome), and subsequently the autophagosome fuses with lysosome forming autolysosome, in which final degradation of cargo material occurs. When the equilibrium between the autophagosome formation and degradation is not maintained, cells undergo stressful conditions that result in cellular damage, dysfunction, and cell death. We observed that SFA induces impaired lysosomal degradation (inhibition of autophagic flux). Cells treated with SFA show increased lipid droplets and pro-inflammatory responses that are associated with inhibition of autophagic flux. We recently generated endothelial specific autophagy gene 7 knockout mice (ATG7-EndKO) to examine the role of endothelial autophagy in endothelial function and nutrient metabolism. ATG7-EndKO mice fed low fat diet do not exhibit impaired glucose tolerance. However, high fat diet (HFD) fed ATG7-EndKO mice exhibit impaired glucose tolerance when compared with control HFD-fed mice. From these results, we hypothesized that endothelial autophagy plays a protective role in SFA-induced endothelial dysfunction and metabolic disorders. To address this hypothesis, we propose to test the following three specific aims. The first aim is to determine the mechanisms by which SFAs impair autophagic flux. We will identify the pathway(s) contributing to SFA-induced impairment of authopagic flux. The second aim is to determine whether impaired autophagy contributes to SFA-induced endothelial dysfunction. The goal of this aim is to understand the role of endothelial autophagy in NO bioavailability. The thir aims to determine whether impaired autophagy contributes to HFD- induced insulin resistance and dyslipidemia in vivo. The results will broaden the knowledge of the pathophysiological consequences of impaired endothelial autophagy in normal and metabolically stressed conditions. Accomplishment of these aims will contribute to understanding the novel mechanisms for SFA- induced endothelial dysfunction, and the role of endothelial autophagy in endothelial function and metabolic homeostasis. Thus, the results may help us to develop a novel therapeutic target to prevent and/or treat obesity-associated vascular complications and metabolism.