Each year, cardiovascular disease (CVD) kills more Americans than any other cause of death. The majority of the diseases contributing to CVD can be traced back to the pathological process of atherosclerosis, in which fatty material collects along the walls of arteries, limiting flexibility and obstructing blood flow. Plasma lipids, particularly in the form of low-density lipoprotein (LDL) cholesterol, contribute significantly to the formation of atherosclerotic plaques and are important determinants of CVD risk. Thus, it is critical to understand the roles of the crucial components of normal lipoprotein metabolism that regulate plasma lipids, such as apolipoprotein (apo) B, apoE and the LDL receptor. In addition, patients with diabetes are two to four times as likely to develop CVD as non-diabetic patients. One important reason for this discrepancy is the process of diabetic dyslipidemia - a cluster of harmful changes to normal lipoprotein metabolism commonly seen in patients with diabetes. ApoE is the primary ligand for several lipoprotein receptors, making it a crucial component in the clearance of lipid from the circulation and a major determinant of plasma cholesterol and cardiovascular disease risk. The APOE gene is polymorphic, resulting in three common isoforms: ApoE2, E3, and E4. In addition to its role in lipoprotein metabolism, recent findings have also suggested a role for ApoE in glucose metabolism. In Chapter 2, I examine the role of apoE3 and apoE4 during the process of diabetic dyslipidemia and atherosclerosis. Similarly, Chapter 3 focuses on the crucial interaction between apoE and the LDLR in the background of diabetes. In Chapter 4, I explore the increased risk of CVD in patients with diabetes in detail, focusing on the various models of diabetic atherosclerosis available to researchers and how they may help understand the cause of this risk. Finally, in Chapter 6 I provide a supplemental examination of the the role of apoB, and in particular the LDLR binding region of apoB100, in the development of hyperlipidemia and atherosclerosis. Together, this work highlights the importance and interconnectedness of glucose and lipid metabolism, and sheds new light on the critical role of apolipoprotein E in the development of dyslipidemia and atherosclerosis during diabetes
