Objectives—: Patients with mutations in the proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) gene have hypercholesterolemia and are at high risk of adverse cardiovascular events. We aimed to stably express the pathological human D374Y gain-of-function mutant form of PCSK9 ( PCSK9 ^DY ) in adult wild-type mice to generate a hyperlipidemic and proatherogenic animal model, achieved with a single systemic injection with adeno-associated virus (AAV). Approach and Results—: We constructed an AAV-based vector to support targeted transfer of the PCSK9 ^DY gene to liver. After injection with 3.5×10 ¹⁰ viral particles, mice in the C57BL/6J, 129/SvPasCrlf, or FVB/NCrl backgrounds developed long-term hyperlipidemia with a strong increase in serum low-density lipoprotein. Macroscopic and histological analysis showed atherosclerotic lesions in the aortas of AAV- PCSK9 ^DY mice fed a high-fat-diet. Advanced lesions in these high-fat-diet–fed mice also showed evidence of macrophage infiltration and fibrous cap formation. Hepatic AAV- PCSK9 ^DY infection did not result in liver damage or signs of immunologic response. We further tested the use of AAV- PCSK9 ^DY to study potential genetic interaction with the ApoE gene. Histological analysis of ApoE ^−/− AAV- PCSK9 ^DY mice showed a synergistic response to ApoE deficiency, with aortic lesions twice as extensive in ApoE ^−/− AAV- PCSK9 ^DY -transexpressing mice as in ApoE ^−/− AAV- Luc controls without altering serum cholesterol levels. Conclusions—: Single intravenous AAV- PCSK9 ^DY injection is a fast, easy, and cost-effective approach, resulting in rapid and long-term sustained hyperlipidemia and atherosclerosis. We demonstrate as a proof of concept the synergy between PCSK9 ^DY gain-of-function and ApoE deficiency. This methodology could allow testing of the genetic interaction of several mutations without the need for complex and time-consuming backcrosses.

Background:Exaggerated and prolonged postprandial triglyceride concentrations are associated with numerous conditions related to insulin resistance, including obesity, type 2 diabetes, and the metabolic syndrome. Although dietary fats profoundly affect postprandial hypertriglyceridemia, limited data exist regarding their effects on postprandial glucose homeostasis. Objective:We sought to determine whether postprandial glucose homeostasis is modulated distinctly by high-fat meals enriched in saturated fatty acids (SFAs) or monounsaturated fatty acids (MUFAs). Design:Normotriglyceridemic subjects with normal fasting glucose and normal glucose tolerance were studied. Blood samples were collected over the 8 h after ingestion of a glucose and triglyceride tolerance test meal (GTTTM) in which a panel of dietary fats with a gradual change in the ratio of MUFAs to SFAs was included. On 5 separate occasions, basal and postprandial concentrations of glucose, insulin, triglyceride, and free fatty acids (FFAs) were measured. Results:High-fat meals increased the postprandial concentrations of insulin, triglycerides, and FFAs, and they enhanced postprandial β cell function while decreasing insulin sensitivity (as assessed with different model-based and empirical indexes: insulinogenic index, insulinogenic index/homeostasis model assessment of insulin resistance, area under the curve for insulin/area under the curve for glucose, homeostasis model assessment for β cell function, and GTTTM-determined insulin sensitivity, oral glucose insulin sensitivity, and the postprandial Belfiore indexes for glycemia and blood FFAs. These effects were significantly ameliorated, in a direct linear relation, when MUFAs were substituted for SFAs. Conclusions:The data presented here suggest that β cell function and insulin sensitivity progressively improve in the postprandial state as the proportion of MUFAs with respect to SFAs in dietary fats increases.

Traditionally, nutrients such as fatty acids have been viewed as substrates for the generation of high-energy molecules and as precursors for the biosynthesis of macromolecules. However, accumulating data from multiple lines of evidence suggest that dietary fatty acids are linked not only to health promotion but also to disease pathogenesis. Metabolism in humans is regulated by complex hormonal signals and substrate interactions. For many years, the clinical focus has centered on a wide metabolic picture after an overnight fast. Nonetheless, the postprandial state (i.e., "the period that comprises and follows a meal") is an important one, and silent disturbances in this period are involved in the genesis of numerous pathological conditions, including atherosclerosis. In this review article, we present an overview of the evidence demonstrating the relevance of oleic acid in olive oil on different nutrition-related issues. We also discuss the impact of oleic acid in olive oil and its clinical relevance to major risk factors for cardiovascular disease in the context of the postprandial state and with regard to other dietary fatty acids.

Background: The nature of dietary fats and fasting concentrations of triglycerides affect postprandial hypertriglyceridemia and glucose homeostasis.