Abstract 13123: Global Knockout of LDLRAP1 Regulates Atherosclerosis, Adipose Metabolism, and Insulin Resistance

Abstract

Introduction: Atherosclerotic vascular syndromes account for 50% of all deaths in the United States, and are a considerable medical and socioeconomic problem contributing to mortality of several conditions, including myocardial infarction and stroke. It is accepted that atherosclerosis and symptoms of metabolic syndrome, such as obesity, insulin resistance, and hypercholesterolemia often coincide with and exacerbate one another, however the molecular events in common with these conditions are not yet fully understood. One event that may link these two disorders is lipid receptor trafficking and signaling of the LDL receptor (LDLR), which plays a key role in LDL uptake and regulation of plasma LDL concentration. Low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) is a cytosolic adaptor protein which interacts with the cytoplasmic tail of the LDLR, mediating internalization of the LDL-LDLR complex and connecting it to the cell’s endocytic machinery. The purpose of this study was to characterize the effects of LDLRAP1 global knockout on atherogenesis and metabolic function in order to gain a better understanding of the molecular mechanisms that interconnect atherosclerosis and metabolic syndrome. Results: LDLRAP1 global knockout mice fed a high-fat western diet (HFD) for 16 weeks displayed increased atherosclerotic plaque burden (p<0.0001), serum cholesterol (p<0.0001) and triglyceride levels (p<0.01), and expression of lipid receptors SR-A1 and CD36 (p<0.05), and gained significantly more weight compared to controls (p<0.0001). LDLRAP1 -/- adipose also displayed decreased glucose uptake (p<0.01) and pAKT and AKT protein levels (p<0.05). Both before and after a HFD, LDLRAP1 -/- mice were also significantly insulin resistant (p<0.01) with concomitant dysregulated insulin signaling in adipose tissue, and displayed metabolic differences as quantified by metabolic cage analysis (p<0.05). Conclusions: These data suggest that in addition to a function in cholesterol internalization, LDLRAP1 participates in regulating adipose metabolism and insulin sensitivity. This implicates LDLRAP1 as a key molecule and potential therapeutic target in treatment of diseases which constitute metabolic syndrome.