The long-term goal of our research is to improve the understanding of the complex regulation of lipid metabolism and to identify potential targets for the treatment of diabetic dyslipidemia. Diabetic dyslipidemia is characterized by elevated plasma triglyceride, reduced high-density lipoprotein (HDL) and often smaller and denser low-density lipoprotein (LDL). Such atherogenic lipid profile significantly increases the risk of cardiovascular disease (CVD), which accounts for ~75% of all mortality in diabetes, underscoring the need to effectively manage dyslipidemia in diabetes. Hypertriglyceridemia is an independent risk factor for CVD. The goal of this project is to define the novel role of hepatic Sortilin 1 (Sort1) in the regulation of plasma triglyceride metabolism in obesity and diabetes. Sort1 is a trans-membrane receptor that regulates the transport, secretion or degradation of cellular proteins in various biological processes. The key discovery that has led to this proposed research is that recent genome-wide association analyses identified very strong and reproducible association of SORT1 gene with plasma LDL cholesterol, triglyceride and CVD risk in large human populations, and that increasing hepatic Sort1 levels caused marked reduction of plasma lipids in mice. However, the mechanisms by which hepatic Sort1 regulates plasma lipids is not fully clear. In addition, current knowledge on how hepatic Sort1 is regulated is stil lacking. Given such knowledge gaps in the field, this proposed study aims to address two questions: First, how does liver Sort1 lower plasma triglyceride? Second, what causes significantly reduced hepatic Sort1 in obesity and diabetes? This study will address these questions by testing the following central hypothesis: Hepatic Sort1 interacts with and promotes the secretion of ApoA5, which activates lipoprotein lipase to stimulate plasma TG clearance and thus lowers plasma TG. In obesity and diabetes, chronic activation of inflammatory signaling and impaired insulin signaling reduce hepatic Sort1 via promoting posttranslational protein degradation, and decreased hepatic Sort1 may contribute to the development and progression of hypertriglyceridemia in obesity and diabetes. Specific aim 1 will use liver-specific Sort1 gain-of-function and loss-of-function mouse models to define the effects and mechanisms of hepatic Sort1 regulation of plasma triglyceride metabolism. Specific aim 2 will delineate the molecular mechanisms of posttranslational down-regulation of liver Sort1 in obesity and diabetes. Specifically, this aim will investigate how inflammation and insulin resistance impair hepatic Sort1 function by altering Sort1 posttranslational modifications, cellular transport process and protein stability. It is expected that this research will provide new mechanistic insights into the strong link between hepatic Sort1 and plasma lipids in humans, and the potential new implications of hepatic Sort1 in the pathogenesis and treatment of diabetic dyslipidemia.