Abstract 10706: Alpha Aminoadipic Acid Down-Regulates Sr-bi Abca1 and Abcg1 Expression and May Regulate Plasma Lipid Profiles, Cellular Cholesterol Efflux, and Efferocytosis

Introduction: The metabolite α-aminoadipic acid (2-AAA) has been identified as a predictor of diabetes and atherosclerosis in large human prospective studies. However, the mechanisms linking this metabolite to disease pathophysiology remain unknown. Efferocytosis, a macrophage-mediated process for clearance of apoptotic cells (ACs), is critical in preventing necrosis of dead cells and triggers anti-inflammatory and pro-resolving responses in phagocytes. Cholesterol efflux from peripheral cells in atherosclerotic plaque is a critical step in Reverse Cholesterol Transport (RCT). We hypothesized that the 2-AAA pathway relates to atherosclerosis through modulation of plasma lipid profiles, cholesterol efflux, and macrophage efferocytosis. Results: We found a significant negative correlation between plasma 2-AAA and HDL cholesterol (r=-0.53, P<0.0001), and a significant positive correlation with triglycerides (r=0.35, P=0.006), in two separate samples of individuals with and without cardiometabolic disease (N=98), suggesting a relationship between 2-AAA and cardiovascular risk. We investigated the consequences of 2-AAA stimulation in several primary cells and cell lines. We found that 2-AAA stimulation downregulates three key genes (SR-BI (up to 86% reduction, P=0.005), ABCA1 (up to 92% reduction, P=0.007), ABCG1 (up to 94% reduction, P=0.008)) that directly relate to cholesterol efflux in THP-1 macropohages, suggesting an important role of 2-AAA in cholesterol efflux. Next, we found that treatment with 2-AAA at physiologically-relevant doses (30μM and 100μM) for times ranging from 30 minutes to 6 hours led to consistent reductions of efferocytosis of up to 60% (P<0.001) in mouse macrophages, J774 cells and Raw 264.7 cells, suggesting a pivotal role of 2-AAA in efferocytosis. Conclusions: Our data suggest 2-AAA is associated with plasma lipid profiles (HDL, triglycerides), cholesterol efflux, and macrophage efferocytosis. These novel data could provide a new target for the treatment of atherosclerosis.