Deletion of LDLRAP1 Induces Atherosclerotic Plaque Formation, Insulin Resistance, and Dysregulated Insulin Response in Adipose Tissue

Abstract

Hypercholesterolemia, vascular inflammation, obesity, and insulin resistance often overlap and exacerbate each other. Mutations in low density lipoprotein receptor adaptor protein‐1 (LDLRAP1) lead to LDL receptor malfunction and are associated with the Autosomal Recessive Hypercholesterolemia (ARH) disorder in humans; however, direct causality on atherogenesis in a defined pre‐clinical model has not been reported. The objective of this study was to test the hypothesis that deletion of LDLRAP1 will lead to hypercholesteremia and atherosclerosis. LDLRAP1‐/‐ mice fed a high‐fat western diet (HFD) had significantly increased plasma cholesterol and triglyceride concentrations (p<0.001), accompanied with significantly increased plaque burden compared with wild‐type controls. Unexpectedly, LDLRAP1‐/‐ mice gained significantly more weight compared with controls (p<0.001), and even on a chow diet, LDLRAP1‐/‐ mice are insulin resistant, and calorimetric studies suggests an altered metabolic profile. We determined that LDLRAP1 is highly expressed in white adipose tissue (VAT), and LDLRAP1‐/‐ adipocytes are significantly larger (p<0.01), and have reduced glucose uptake and AKT phosphorylation, but increased CD36 expression. VAT from LDLRAP1‐/‐ mice is hypoxic and has gene expression signatures of dysregulated lipid storage and energy homeostasis. These data are the first to indicate that lack of LDLRAP1 directly leads to atherosclerosis in mice and also plays an unanticipated metabolic regulatory role in adipose tissue. LDLRAP1 may link atherosclerosis and hypercholesterolemia with common co‐morbidities of obesity and insulin resistance.