Project 3: Triglycerides, lipolysis, and vascular inflammation

University Of Washington, Seattle WA

Investigators

Linked publications & trials

Abstract

Diabetes is associated with greater cardiovascular disease (CVD), likely due, at least in part, to increased circulating levels of atherogenic lipoproteins. The most common dyslipidemia in patients with diabetes, especially type 2 diabetes (T2D), is hypertriglyceridemia (hyperTG). Human data implicate genes associated with hyperTG, such as lipoprotein lipase (LPL), apolipoprotein C3 (APOC3), and angiopoietin-like protein (ANGPTL)3, with CVD. Despite more than 4 decades of investigation, a mechanistic understanding of the relationship between hyperTG and CVD has not been clearly defined. Although partially degraded remnant triglyceride-rich lipoproteins (TRLs) have been proposed as especially atherogenic entities, we provide in vitro and in vivo data implicating TRLs from LPL-deficient mice as a cause of endothelial cell (EC) inflammation. Moreover, we have found that TRL uptake by ECs is mediated by a specific region in the N-terminal region of apolipoprotein (APO) B. Project 3 of this PPG proposes to use two models of diabetes to assess how hyperTG heightens EC inflammation and dampens atherosclerosis regression. Our studies will determine if uptake of lipoproteins via scavenger receptor-BI (SR-BI) and activin receptor kinase l (ALK1) leads to different downstream consequences under diabetic conditions. In addition, we will determine the lipid uptake pathway and lipolysis processes required for the benefit of eicosapentaenoic acid (EPA) to reduce CVD events in patients with diabetes, as recently shown in the REDUCE-IT trial. We will study how hyperchylomicronemia and macrophage (MΦ)-specific LPL deficiency affect the production of resolving lipids from EPA and the phenotype of vascular cells. Our studies will determine if lipoproteins that are altered in diabetes prevent normal atherosclerosis regression after lipid lowering, leading to information that will inform clinical trials of new methods to reduce APOC3 and ANGPTL3. In addition, we will provide insights on EPA biology that will inform the on-going debate on the possible clinical utility of the use of EPA in CVD. This Project proposes to answer two questions: Aim 1: Do TRLs and their route of EC uptake lead to different effects on atherosclerosis regression in diabetic mice? We will assess how APOB48 and APOB100 lipoprotein uptake via ALK1 and SR-BI affect arterial ECs under diabetic conditions. In addition, the contributions of APOC3 and ANGPTL3 to changes in circulating lipoprotein properties will be considered. These data will inform our studies of regression in diabetic mice. Aim 2: Are the beneficial effects of EPA- containing TRLs due to their EC uptake and subsequent creation of resolving lipids by plaque Mϕs? We will use generalized inducible- and MΦ-specific LPL knockout to determine how liberation of EPA from TGs affects production of resolving lipids and atherosclerosis regression during diabetes. These studies will involve extensive interactions with the other projects of this PPG and use of Cores B and C.