Plasma lipoproteins are the major vehicles for non-aqueous transport of lipids, including cholesterol and triglyceride, and lipid-soluble vitamins such as vitamin A and E, from the liver and intestine to tissues. Derangements in lipoprotein metabolism are involved in progression of atherosclerosis, an underlying cause of heart disease and strokes which remain the major cause of death in the United States. Insulin, known as a key regulator in carbohydrate metabolism, plays a major regulatory role in hepatic lipoprotein metabolism. Insulin acts by inhibition of secretion of triglyceride-rich lipoproteins through a mechanism involving the stimulation of the intracellular degradation of apolipoprotein B, an essential structural apolipoprotein. Research in my laboratory links specific events involved in insulin receptor (IR) signal transduction with microsomal events that lead to degradation of apo B. The focus is on insulin-activated phosphatidylinositide 3-kinase (PI-3-kinase) in the translocation of apo B and its intracellular transport within the secretory pathway. Investigations employ primary rat hepatocytes, McArdle RH-7777 rat hepatoma cells and HepG2 cells and assay of IR signaling, Beta-subunit phosphorylation, IRS phosphorylation, PI 3-K activation and of PI 3-K mass in subcellular fractions. Progress will allow better understanding of insulin regulation of triglyceride-rich lipoprotein secretion by liver and will provide insights into the mechanisms involved in the development of hypertriglyceridemia in human obesity and insulin resistance syndromes such as metabolic Syndrome X which increase the risk of atherosclerosis complications up to ten times.